Fused heterocyclic compounds and pharmaceutical applications thereof

ABSTRACT

The present invention relates to a fused heterocyclic compound of the formula (I)                    
     wherein each symbol is as defined in the specification, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing a compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and a medicament containing a compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. The compound of the present invention is a useful antipsychotic agent effective not only for positive symptoms centering on hallucination and delusion characteristic of the acute stage of schizophrenia, but also negative symptoms of apathy, abulia and autism. The inventive compound is expected to make a highly safe antipsychotic agent associated with less side effects, such as extrapyramidal symptoms and endocrine disturbance, which are observed when a conventional antipsychotic agent having a D 2  receptor blocking action is administered. Therefore, the inventive compound can be used as a therapeutic agent for the diseases such as schizophrenia.

TECHNICAL FIELD

The present invention relates to a novel fused heterocyclic compoundhaving affinity for dopamine D₄ (hereinafter to be referred to as D₄,the same abbreviation to be employed with regard to the followingdopamine receptor subtypes) receptor and serotonin 2 (hereinafter to bereferred to as 5-HT₂) receptor, which blocks NMDA receptor hypofunction,and which is used in the medical field as a central nervous agent,particularly as an antipsychotic agent.

BACKGROUND ART

The following patent applications have been published with regard tocentral nervous agents having affinity for D₄ receptor. WO94/10162,WO94/21630 and WO94/21626 disclose heterotricyclic aromatic compoundshaving affinity for D₄ receptor; WO94/21627, WO94/21628 and WO94/24105disclose indole derivatives having affinity for D₄receptor; WO94/20459and WO94/20497 disclose pyrropyridine derivatives having affinity for D₄receptor; and WO94/21615 and WO94/22839 disclose benzimidazolderivatives having affinity for D₄ receptor. WO94/10145 and WO94/20471disclose pyrazole derivatives and quinolone derivatives each havingaffinity for D₄ receptor.

Japanese Patent Unexamined Publication No. 157576/1979 discloses thatcydoalkyltriazoles represented by dapiprazole[3-(2-(4-(2-tolyl)-1-piperazinyl)ethyl)-5,6,7,8-tetrahydro-s-triazole-[4,3-a]pyridine]can be used for the therapy of glaucoma, psychosis and the like.

Almost all antipsychotic agents applicable to schizophrenia show acommon pharmacological action of blocking the receptor of dopamine whichis one of the cerebral neurotransmitters, and exhibit particularlypotent D₂ receptor blocking action. These medicaments (typicalantipsychotic agents) are effective against positive symptoms centeringon hallucination and delusion characteristic of the acute stage ofschizophrenia, but are barely effective against negative symptoms ofapathy, abulia and autism. In addition, they are associated with seriousproblems of side effects such as extrapyramidal symptoms (e.g., delayeddyskinesia, acute dystonia, akathisia, etc.) and endocrine disturbance(e.g., hyperprolactinemia) observed upon acute administration and longterm consecutive administration.

Dopamine receptor has been conventionally classified into two receptorsubtypes by pharmacological methods according to the type of ligandbinding and association mode with adenylate cyclase [Nature, vol. 227,p. 93 (1979)]. That is, a D₁ receptor type that promotes adenylatecyclase via acceleratory G protein to produce cyclic AMP, and a D₂receptor type that suppresses adenylate cyclase via suppressive Gprotein to suppress production of cyclic AMP. Due to the revolutionarydevelopment of molecular biology in recent years, five different genesof dopamine receptors were cloned and the dopamine receptors are nowclassified into D₁ and D₅ receptors belonging to the D₁ fans, and D₂, D₃and D₄ receptors belonging to the D₂ family [Trends in Pharmacol. Sci.,vol. 15, p. 264 (1994)].

It has been documented that haloperidol, which is a typicalantipsychotic agent, has higher affinity for D₂ receptor than for D₄receptor, and clozapine, which is associated with less extrapyramidalside effects and also effective against negative symptoms, has 10 timeshigher affinity for D₄ receptor than for D₂ receptor [Nature, vol. 350,p. 610 (1991)], [Trends in Pharmacol. Sci., vol. 15, p. 264 (1994)]. Ithas been also reported that the effective therapeutic plasmaconcentration of clozapine correlates with the affinity constant for D₄receptor [Trends in Pharmacol. Sci., vol. 15, p. 264 (1994)]. A reporthas been documented on a binding test using the postmortem brain of aschizophrenic patient, that D₄ receptor showed 6 times greater levelthan in a healthy subject [Nature, vol. 365, p. 441 (1993)]. Therefromit appears that D₄ receptor highly likely causes schizophrenia or ispresent at the action site of a therapeutic agent. There have been foundvariations in the distribution of dopamine receptor in the brain due tosubtypes, wherein D₂ receptor is most frequently found in the corpusstriatum, and D₄ receptor is most often found in the frontal lobe ofcerebral cortex which is responsible for the emotional functions.

From clinical applications, it has been made clear that the concurrentuse of ritanserin (which is a 5-HT₂ receptor blocker) with a typicalantipsychotic agent improves negative symptoms and emotional disorderssuch as anxiety [Current Therapeutics Research, vol. 10, p. 492 (1986)].Of the side effects caused by antipsychotic agents, malignant syndromesthat are most serious and deadly, though low in incidence is, accordingto one hypothetical view, caused by the imbalance of dopamine/serotoninnervous functions in the body temperature control center [JapaneseJournal of Psychopharmacology, vol. 11, p. 17 (1989)], and suppressionof the onset of the disease by the application of the 5-HT₂ receptorblocking action is expected.

There is also a hypothetical view on the cause of schizophrenia, thatsays that the degradation of the function of the NMDA(N-methyl-D-aspartic acid) nervous system that is projected from thecerebral cortex to subcortex impairs the suppressive feed-back functionof the information control circuit, which in turn aggravates theschizophrenia state, like the excessive promotion of the activity of thesubcortical dopamine nervous system, and clozapine has been reported toshow blockage of NMDA receptor hypofunction besides the action ondopamine and serotonin nervous systems [Trends Neurosci., vol. 13, p.272 (1990)].

From the foregoing, a compound having a D₄ receptor and 5-HT₂ receptorblocking action, and which blocks NMDA receptor hypofunction, isexpected to make an antipsychotic agent associated with lessextrapyramidal side effects and effective against both positive andnegative symptoms. It is therefore an object of the present invention toprovide a compound exhibiting strong blocking action on D₄ receptor and5-HT₂ receptor, as well as blockage of NMDA receptor hypofunction, whichis effective against both negative symptoms and positive symptoms ascompared to conventional compounds and which is associated with lessside effects.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies and found that anovel fused heterocyclic compound of the following formula (I), anoptical isomer thereof and a pharmaceutically acceptable salt thereofhave stronger blocking action on D₄ receptor and 5-HT₂ receptor than onD₂ receptor, and that they show blockage of NMDA receptor hypofunction.The present inventors have further found that these compounds can makeuseful antipsychotic agents effective against not only positive symptomscentering on hallucination and delusion characteristic of the acutestage of schizophrenia, but also negative symptoms of apathy, abulia andautism, that cause less side effects such as extrapyramidal symptoms andendocrine disturbance observed when conventional antipsychotic agentshaving D₂ receptor blocking action are administered, which resulted inthe completion of the present invention.

Accordingly, the present invention relates to a fused heterocycliccompound of the formula (I)

wherein

R is a group selected from the group consisting of the groups having thefollowing formulas (1), (2), (3), (4), (5), (6), (7), (8) and (9)

wherein

Y is a linear or branched C₁-C₄ alkylene optionally having a substituent

R^(1a) at an optional position, wherein R^(1a) is hydrogen, alkyl,hydroxy, alkoxy, amino or alkylamino,

A is void, or an oxygen atom, a sulfur atom, SO, SO₂ or N—R⁷ wherein R⁷is hydrogen, alkyl, arylalkyl or acyl,

B is a linear or branched C₁-C₄ alkylene optionally having a substituent

R^(1b) at an optional position, wherein R^(1b) is hydrogen, alkyl,hydroxy, alkoxy, amino or alkylamino,

R^(2a), R^(2b) and R^(2c) are the same or different and each is ahydrogen or an alkyl,

R³ is a hydrogen, an alkyl, an acyl or an aryl, and

R⁸ is a hydrogen, an acyl or an alkyl;

D is void, or a linear or branched alkylene having 1 to 8 carbon atoms;

Q—T is a bond of CH, CH₂—N, (CH₂)₂—N, CH₂—C(R⁴) wherein R⁴ is hydrogen,hydroxy, alkyl or alkoxy, or CH═C,

provided that when R is a group of the formula (1) and A is void, thebond Q—T is CH, (CH₂)₂—N, CH₂—C(R⁴) wherein R⁴ is as defined above, orCH═C;

G is void, or a linear or branched alkylene having 1 to 8 carbon atomsor a carbonyl;

R⁵ is a hydrogen or an alkyl; and

R⁶ is an optionally substituted aryl, an optionally substitutedheteroaryl or an optionally substituted fused heteroaryl,

an optical isomer thereof or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical compositioncomprising a fused heterocyclic compound of the formula (I), an opticalisomer thereof or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, and a medicament comprising a fusedheterocyclic compound of the formula (I), an optical isomer thereof or apharmaceutically acceptable salt thereof.

The fused heterocyclic compound of the formula (I) includes thefollowing 9 kinds of compounds.

With regard to the above formula (I), alkyl at R^(1a) is, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl and the like, withpreference given to alkyl having 1 to 4 carbon atoms. The alkoxy is, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like, withpreference given to alkoxy having 1 to 4 carbon atoms. The alkylaminois, for example, methylamino, dimethylamino, ethylamino, diethylamino,propylamino, dipropylamino and the like.

The alkyl, alkoxy and alkylamino at R^(1b) are exemplified by thosementioned with respect to alkyl, alkoxy and alkylamino at R^(1a).

The alkyl at R^(2a), R^(2b) and R^(2c) is exemplified by those mentionedwith respect to alkyl at R^(1a).

The alkyl at R³ is exemplified by those mentioned with respect to alkylat R^(1a). The acyl is, for example, formyl, acetyl, propionyl, benzoyl,benzylcarbonyl and the like, with preference given to acetyl. The arylis, for example, phenyl, naphthyl, 2-indanyl and the like, withpreference given to phenyl having 1 or 2 substituent(s), such ashalogen, methyl, trifluoromethyl and methoxy.

The alkyl and alkoxy at R⁴ are exemplified by those mentioned withrespect to alkyl and alkoxy at R^(1a).

The alkyl at R⁵ is exemplified by those mentioned with respect to alkylat R^(1a).

The alkyl at R⁶ is, for example, phenyl, naphthyl, 2-indanyl and thelike. The heteroaryl is, for example, pyridyl, furyl, thienyl,pyrimidinyl and the like. The fused heteroaryl is, for example,1,2-benzoisoxazol-3-yl, 1,2-benzoisothiazol-3-yl, indol-3-yl,benzo[b]furan-3-yl, benzo[b]thiophen-3-yl and the like. The substituenttherefor may be, for example, halogen (e.g., fluorine, chlorine andbromine), haloalkyl (e.g., trifluoromethyl), alkyl (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl and tert-butyl), alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,pentyloxy, hexyloxy, heptyloxy and octyloxy), hydroxy, nitro, amino,methylamino, dimethylamino and the like.

The alkyl at R⁷ is exemplified by those mentioned with respect to alkylat R^(1a). The arylalkyl is, for example, benzyl, 2-phenylethyl,3-phenylpropyl, 2-methyl-2-phenylethyl, 3-methyl-3-phenylpropyl,4-chlorobenzyl, 2-(4-chlorophenyl)ethyl, 3-(4-chlorophenyl)propyl,2-methyl-2-(4-chlorophenyl)ethyl, 3-methyl-3-(4-chlorophenyl)propyl andthe like, with preference given to benzyl. The acyl is, for example,formyl, acetyl, propionyl, benzoyl, benzylcarbonyl and the like, withpreference given to acetyl.

The alkyl at R⁸ is exemplified by those mentioned with respect to alkylat R^(1a). The acyl is exemplified by those mentioned with respect toacyl at R³.

The linear or branched alkylene having 1 to 4 carbon atoms at Y isexemplified by methylene, ethylene, trimethylene, tetramethylene,methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene,1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene,diethylmethylene, 1-ethylethylene, 2-ethylethylene,1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, 3-methyltrimethylene,3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene,3-ethyltrimethylene and the like, with preference given to ethylene andtrimethylene.

The linear or branched alkylene having 1 to 4 carbon atoms at B isexemplified by those mentioned with respect to the linear or branchedalkylene having 1 to 4 carbon atoms at Y.

The linear or branched alkylene having 1 to 8 carbon atoms at D isexemplified by methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, octamethylene, methylmethylene,dimethylmethylene, 1-methylethylene, 2-methylethylene,1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene,diethylmethylene, 1-ethylethylene, 2-ethylethylene,1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, 3-methyltrimethylene,3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene,3-ethyltrimethylene and the like, with preference given to ethylene,trimethylene and tetramethylene.

The linear or branched alkylene having 1 to 8 carbon atoms at G isexemplified by those mentioned with respect to the linear or branchedalkylene having 1 to 8 carbon atoms at D.

The group of the formula

is specifically exemplified by the following groups.

With regard to the formula (I), a preferable compound is the compound

wherein

R is a group selected from the group consisting of the groups having theformulas (1), (2), (3), (4), (5), (6), (7), (8) and (9),

wherein

Y is a linear or branched C₁-C₄alkylene optionally having a substituentR^(1a) at an optional position wherein R^(1a) is hydrogen or alkyl,

A is void, or an oxygen atom, a sulfur atom or N—R⁷ wherein R⁷ ishydrogen, alkyl, arylalkyl or acyl,

B is a linear or branched C₁-C₄ alkylene optionally having a substituent

R^(1b) at an optional position, wherein R^(1b) is hydrogen or alkyl,

R^(2a), R^(2b) and R^(2c) are the same or different and each is ahydrogen or an alkyl,

R³ is a hydrogen, an alkyl, an acyl or an aryl, and

R⁸ is a hydrogen, an acyl or an alkyl;

D is void, or a linear or branched alkylene having 1 to 8 carbon atoms;

Q—T is a bond of CH, CH₂—N, (CH₂)₂—N, CH₂—C(R⁴) wherein R⁴ is hydrogen,hydroxy, alkyl or alkoxy, or CH═C,

provided that when R is a group of the formula (1) and A is void, thebond Q—T is CH, (CH₂)₂—N, CH₂—C(R⁴) wherein R⁴ is as defined above, orCH═C;

G is void;

R⁵ is a hydrogen or an alkyl; and

R⁶ is an optionally substituted aryl, an optionally substitutedheteroaryl or an optionally substituted fused heteroaryl.

With regard to the formula (I), a more preferable compound is thecompound

wherein

R is a group selected from the group consisting of the groups having theformulas (1), (2), (3), (4), (5), (6), (7), (8) and (9),

wherein

Y is a linear alkylene having 1 to 4 carbon atoms,

A is void, or an oxygen atom or N—R⁷ wherein R⁷ is hydrogen or acyl,

B is a linear or branched alkylene having 1 to 4 carbon atoms,

R^(2a), R^(2b) and R^(2c) are the same or different and each is ahydrogen or an alkyl having 1 to 4 carbon atoms,

R³ is a hydrogen, an alkyl having 1 to 4 carbon atoms or an acyl, and

R⁸ is a hydrogen or an alkyl having 1 to 4 carbon atoms;

D is void, or a linear or branched alkylene having 1 to 8 carbon atoms;

Q—T is a bond of CH₂—N, CH₂—C(R⁴) wherein R⁴ is hydrogen, hydroxy, alkylor alkoxy, or CH═C,

provided that when R is a group of the formula (1) and A is void, thebond Q—T is CH₂—C(R⁴) wherein R⁴ is as defined above, or CH═C;

G is void;

R⁵ is a hydrogen or an alkyl having 1 to 4 carbon atoms; and

R⁶ is an optionally substituted aryl, an optionally substitutedheteroaryl or an optionally substituted fused heteroaryl.

With regard to the formula (I), a still more preferable compound is thecompound

wherein

R is a group selected from the group consisting of the groups having theformulas (1), (2), (3), (4), (6), (7) and (8),

wherein

Y is an ethylene,

A is void, or an oxygen atom or N—R⁷ wherein R⁷ is hydrogen or acyl,

B is a linear or branched alkylene having 1 to 3 carbon atoms,

R^(2a) and R^(2b) are the same or different and each is a hydrogen or analkyl having 1 to 4 carbon atoms,

R³ is a hydrogen or an alkyl having 1 to 4 carbon atoms, and

R⁸ is a hydrogen or an alkyl having 1 to 4 carbon atoms;

D is void, or a linear or branched alkylene having 1 to 8 carbon atoms;

Q—T is a bond of CH₂—N, CH₂—C(R⁴) wherein R⁴ is hydrogen, alkyl oralkoxy, or CH═C,

provided that when R is a group of the formula (1) and A is void, thebond Q—T is CH₂—C(R⁴) wherein R⁴ is as defined above, or CH═C;

G is void;

R⁵ is a hydrogen or an alkyl having 1 to 4 carbon atoms; and

R⁶ is an optionally substituted aryl, an optionally substitutedheteroaryl or an optionally substituted fused heteroaryl.

With regard to the formula (I), a particularly preferable compound isthe compound

wherein

R is a group selected from the group consisting of the groups having theformulas (1), (2), (3), (4), (6), (7) and (8),

wherein

Y is an ethylene,

A is void, or an oxygen atom or N—R⁷ wherein R⁷ is hydrogen or acyl,

B is a linear alkylene having 1 to 3 carbon atoms,

R^(2a) and R^(2b) are the same or different and each is a hydrogen or amethyl,

R³ is a hydrogen or a methyl, and

R⁸ is a hydrogen or a methyl;

D is a trimethylene;

Q—T is a bond of CH₂—N, CH₂—CH or CH═C,

provided that when R is a group of the formula (1) and A is void, thebond Q—T is CH₂—CH or CH═C;

G is void;

R⁵ is a hydrogen; and

R⁶ is an aryl optionally having halogen or alkyl having 1 to 4 carbonatoms.

With regard to the formula (I), the most preferable compounds are thoseselected from the following group of compounds wherein the number in theparenthesis corresponds to example number.

(2)3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine,

(3)3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine,

(48)3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole,

(89)3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole,

(90)3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoe,

(104)3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,

(113)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine,

(116)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,

(117)3-(3-(4-(4-methylphenyl)piperin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,

(118)3-(3-(4-phenylpiperazin-1-yl)propyl)4,5,6,7-tetrahydro-2H-indazole,

(137)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole,

(141)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,

(142)5-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,

(153)3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole,

(154)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole,

(155)4,5,6,7-tetrahydro-1-methyl-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-1H-indazole,

(156)4,5,6,7-tetrahydro-1-methyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1H-indazole,

(162)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindoleand

(173)3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydropyrazolo-[2,3-a]pyridine.

The pharmaceutically acceptable salt of the compound of the formula (I)is, for example, acid addition salt with inorganic acid (e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andnitric acid) or organic acid (e.g., acetic acid, propionic add, succinicacid, glycolic acid, lactic acid, malic acid, tartaric acid, citricacid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, camphorsulfonic acid and ascorbic acid).

The compound of the formula (I) and pharmaceutically acceptable saltsthereof may exist in the form of a hydrate or a solvate, and suchhydrate and solvate are also encompassed in the present invention.Examples thereof include 1/10 hydrate, 1/4 hydrate, 1/2 hydrate,monohydrate, dihydrochloride 1/2 hydrate, dihydrochloride dihydrate,dihydrochloride 3/2 hydrate and the like. When the compound of theformula (I) has an asymmetric carbon, at least two kinds of opticalisomers exist. These optical isomers and racemates thereof areencompassed in the present invention.

The compound of the formula (I) and the inventive compounds included inthe formula (I) can be synthesized by the following methods. Each symbolin the following reaction formulas is as defined above unlessspecifically indicated.

1. Compound wherein R is a group of the formula (1):

A compound of the formula (10) is reacted with chlorinating agent (e.g.,phosphorus pentachloride, phosphorus trichloride and phosphorusoxychloride) in a suitable solvent (e.g., benzene, toluene, xylene andmixed solvents of optional members therefrom) at room temperature to therefluxing temperature of the solvent for 1-24 hours to give the compoundof the formula (11). This compound is reacted in a suitable solvent(e.g., methanol, ethanol, butanol, ethylene glycol,N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and mixedsolvents of optional members therefrom) in the presence of a compound ofthe formula (12) at room temperature to 200° C. for 1-24 hours to givethe compound of the formula (I-1).

A compound of the formula (10) is reacted with dimethyl sulfate in asuitable solvent (e.g., benzene, toluene, xylene and mixed solvents ofoptional members therefrom) at the refluxing temperature of the solventfor 1-24 hours to give the compound of the formula (13). This compoundis reacted in a suitable solvent (e.g., methanol, ethanol, butanol,ethylene glycol, N-methyl-2-pyrrolidone, 1,3dimethyl-2-imidazolidinoneand mixed solvents of optional members therefrom) in the presence of acompound of the formula (12) at room temperature to 200° C. for 1-24hours to give the compound of the formula (I-1).

A compound of the formula (10) is reacted with thionating agent (e.g.,phosphorus pentasulfate and Lawesson reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide])in a suitable solvent (e.g., benzene, toluene, xylene and mixed solventsof optional members therefrom) at room temperature to the refluxingtemperature of the solvent for 1-24 hours to give the compound of theformula (14). This compound is reacted in a suitable solvent (e.g.,methanol, ethanol, butanol, ethylene glycol, N-methyl-2-pyrrolidone,1,3-dimethyl-2-imidazolidinone and mixed solvents of optional memberstherefrom) in the presence of a compound of the formula (12) at roomtemperature to 200° C. for 1-24 hours to give the compound of theformula (I-1).

A compound of the formula (14) is reacted with benzyl chloride,p-nitrobenzyl chloride or methyl iodide in a suitable solvent that doesnot interfere with the reaction (e.g., tetrahydrofuran, diethyl ether,dioxane, water and mixed solvents of optional members therefrom) in thepresence of a base such as potassium hydroxide and potassiumtert-butoxide, at room temperature to the refluxing temperature of thesolvent for 1-24 hours to give the compound of the formula (15) whereinR⁹is methyl, benzyl, p-nitrobenzyl and the like and other symbols are asdefined above. This compound is reacted with a compound of the formula(12) in a suitable solvent (e.g., methanol, ethanol, butanol, ethyleneglycol, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone and mixedsolvents of optional members therefrom) at room temperature to 200° C.for 1-24 hours to give the compound of the formula (I-1).

A compound of the formula (16) and a compound of the formula (17) arestirred while heating at 150° C.-200° C. for 1-24 hours to give acompound of the formula (18). This compound is subjected to catalytichydrogenation using a platinum, palladium or nickel catalyst in asuitable solvent that does not interfere with the reaction (e.g.,methylene chloride, chloroform, ethyl acetate, methanol, ethanol andmixed solvents of optional members therefrom) to give the compound ofthe formula (19).

Any one of the compounds of the formulas (11), (13), (14) and (15) isreacted with a compound of the formula (20) wherein R¹⁰ is a protectinggroup inert to the reaction, such as tert-butoxycarbonyl andbenzyloxycarbonyl, and Q—T is (CH₂)₂—N, in a suitable solvent that doesnot interfere with the reaction (e.g., methanol, ethanol, butanol,ethylene glycol, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinoneand mixed solvents of optional members therefrom) at room temperature to200° C. for 1-24 hours to give a compound of the formula (21) whereinQ—T is (CH₂)₂—N and R¹⁰ is as defined above. This compound is subjectedto deprotection by a conventional method using a suitable acid such ashydrochloric acid, hydrobromic acid and trifluoroacetic acid to give acompound of the formula (22) wherein Q—T is (CH₂)₂—N and R¹⁰ is asdefined above. This compound or an acid addition salt thereof, such ashydrochloride, hydrobromide, sulfate and oxalate, is reacted with acompound of the formula (23) wherein L is chlorine, bromine, iodine,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxyand the like, in a suitable solvent that does not interfere with thereaction (e.g., tetrahydrofuran, dichloromethane, dimethylformamide andmixed solvents of optional members therefrom) in the presence of a basesuch as potassium carbonate, sodium hydroxide, triethylamine, pyridineand dimethylaminopyridine, from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (I-1) wherein Q—T is(CH₂)₂—N.

Method (7)

Any one of the compounds of the formulas (11), (13), (14) and (15) isreacted with a compound of the formula (24) in a suitable solvent thatdoes not interfere with the reaction (e.g., methanol, ethanol, butanol,ethylene glycol, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinoneand mixed solvents of optional members therefrom) at room temperature to200° C. for 1-24 hours to give a compound of the formula (25). Thiscompound is reacted with p-toluenesulfonyl chloride or methanesulfonylchloride in a suitable solvent that does not interfere with the reaction(e.g., methylene chloride, chloroform and dichloroethane) in thepresence of a base such as triethylamine to introduce a leaving group.The resulting compound is reacted with a compound of the formula (26) oran acid addition salt thereof, such as hydrochloride, hydrobromide,sulfate and oxalate, in a suitable solvent that does not interfere withthe reaction (e.g., methylene chloride, chloroform, dichloroethane,tetrahydrofuran, diethyl ether and mixed solvents of optional memberstherefrom) in the presence of a suitable base such as potassiumcarbonate, pyridine and triethylamine, at room temperature to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (I-1).

2. Compound wherein R is a group of the formula (2):

Using a compound of the formula (27) obtained by the method described inEur. J. Med. Chem., vol. 10, p. 528 (1975) and in accordance with themethod described in Japanese Patent Unexamined Publication No.189179/1983, a compound of the formula (28) is obtained. This compoundis reacted with a compound of the formula (26) using a fusing agent suchas 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (29). When a reactivederivative (acid chloride and acylimidazol) of the compound of theformula (28) is used, the reaction proceeds in a suitable solvent thatdoes not interfere with the reaction (e.g., tetrahydrofuran,dichloromethane, chloroform, benzene and mixed solvents of optionalmembers therefrom) in the presence of a tertiary amine such astriethylamine or pyridine from under ice-cooling to room temperature for1-24 hours.

The compound of the formula (29) thus obtained is reduced in a suitablesolvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, toluene and mixed solvents of optionalmembers therefrom) using a reducing agent such as lithium aluminumhydride and borane at −78° C. to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (I-2) wherein Dis trimethylene.

A compound of the formula (30) wherein E is a liner or branched alkylenehaving 1 to 7 carbon atoms, which is obtained by the method described inJ. Med. Chem., vol. 12, p. 122 (1969) is subjected to catalytichydrogenation using a platinum, palladium or nickel catalyst in asuitable solvent that does not interfere with the reaction (e.g.,methylene chloride, chloroform, ethyl acetate, methanol, ethanol andmixed solvents of optional members therefrom) to give the compound ofthe formula (31). This compound is reacted with a compound of theformula (26) using a fusing agent such as 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (32). When a reactivederivative (acid chloride and acylimidazol) of the compound of theformula (31) is used, the reaction proceeds in a suitable solvent thatdoes not interfere with the reaction (e.g., tetrahydrofuran,dichloromethane, chloroform, benzene and mixed solvents of optionalmembers therefrom) in the presence of a tertiary amine such astriethylamine or pyridine from under ice-cooling to room temperature for1-24 hours.

The compound of the formula (32) thus obtained is reduced in a suitablesolvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, toluene and mixed solvents of optionalmembers therefrom) using a reducing agent such as lithium aluminumhydride and borane at −78° C. to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (33).

A compound of the formula (30) wherein E is a linear or branchedalkylene having 1 to 7 carbon atoms) is reacted with a compound of theformula (26) using a fusing agent such as 1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (34). When a reactivederivative (acid chloride and acylimidazol) of the compound of theformula (30) is used, the reaction proceeds in a suitable solvent thatdoes not interfere with the reaction (e.g., tetrahydrofuran,dichloromethane, chloroform, benzene and mixed solvents of optionalmembers therefrom) in the presence of a tertiary amine such astriethylamine or pyridine from under ice-cooling to room temperature for1-24 hours.

The compound of the formula (34) thus obtained is reduced in a suitablesolvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, toluene and mixed solvents of optionalmembers therefrom) using a reducing agent such as lithium aluminumhydride and borane at −78° C. to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (35). Thiscompound is subjected to catalytic hydrogenation using a platinum,palladium or nickel catalyst in a suitable solvent that does notinterfere with the reaction (e.g., methylene chloride, chloroform, ethylacetate, methanol, ethanol and mixed solvents of optional memberstherefrom) to give the compound of the formula (33).

3. Compound wherein R is a group of the formula (3) or (4):

A compound of the formula (36) is reacted with a compound of the formula(37) wherein J is chlorine, imidazole, cyano and the like in a suitablesolvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, methylene chloride, chloroform,dimethylformamide and mixed solvents of optional members therefrom) inthe presence of a suitable dehydrogenating agent (e.g., lithiumdiisopropylamide, lithium bistrimethylsilylamide, potassium t-butoxideand triethylamine) from −78° C. to under ice-cooling for 1-24 hours togive a compound of the formula (38). This compound is reacted in asuitable solvent (e.g., methanol, ethanol, butanol, ethylene glycol,methylene chloride, chloroform and mixed solvents of optional memberstherefrom) in the presence of a compound of the formula (39) at roomtemperature to the refluxing temperature of the solvent for 1-24 hoursto give a compound of the formula (I-3) or the formula (I-4).

According to the method described in Org. Syntheses. Coll., Vol. 5, p.808 (1973), an examine compound of the formula (40) can be obtained froma compound of the formula (36) and secondary amine (e.g., morphoine,pyrrolidine and piperidine). According to the method described inSynthesis, p. 510 (1970), a compound of the formula (38) can be obtainedfrom this compound and a compound of the formula (37). This compound isreacted in a suitable solvent (e.g., methanol, ethanol, butanol,ethylene glycol, methylene chloride, chloroform and mixed solvents ofoptional members therefrom) in the presence of a compound of the formula(39) at room temperature to the refluxing temperature of the solvent for1-24 hours to give a compound of the formula (I-3) or the formula (I-4).

A compound of the formula (41) obtained by the method described inChemische Berichte, vol. 92, p. 652 (1959) is reacted with a compound ofthe formula (26) using a fusing agent such as1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (42). When a reactivederivative (acid chloride and acylimidazol) of the compound of theformula (41) is used, the reaction proceeds in a suitable solvent thatdoes not interfere with the reaction (e.g., tetrahydrofuran,dichloromethane, chloroform, benzene and mixed solvents of optionalmembers therefrom) in the presence of a tertiary amine such astriethylamine or pyridine from under ice-cooling to room temperature for1-24 hours.

This compound is reacted in a suitable solvent (e.g., methanol, ethanol,butanol, ethylene glycol, methylene chloride, chloroform and mixedsolvents of optional members therefrom) in the presence of a compound ofthe formula (39) at room temperature to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (43) or (44) ora mixture thereof. In the case of a mixture, it can be separated by apurification method such as silica gel column chromatography andrecrystallization. The compound of the formula (43) or (44) thusobtained is reduced in a suitable solvent that does not interfere withthe reaction (e.g., tetrahydrofuran, diethyl ether, toluene and mixedsolvents of optional members therefrom) using a reducing agent such aslithium aluminum hydride and borane at −78° C. to the refluxingtemperature of the solvent for 1-24 hours to give a compound of theformula (45) or (46).

A compound of the formula (41) is reacted in a suitable solvent (e.g.,methanol, ethanol, butanol, ethylene glycol, methylene chloride,chloroform and mixed solvents of optional members therefrom) in thepresence of a compound of the formula (39) at room temperature to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (47) or (48) or a mixture thereof. This compound isreacted with a compound of the formula (26) using a fusing agent such as1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (43) or(44) or amixture thereof. In the case of a mixture, it can be separated by apurification method such as silica gel column chromatography andrecrystallization. When a reactive derivative (acid chloride andacylimidazol) of the compound of the formula (47) or (48) is used, thereaction proceeds in a suitable solvent that does not interfere with thereaction (e.g., tetrahydrofuran, dichloromethane, chloroform, benzeneand mixed solvents of optional members therefrom) in the presence of atertiary amine such as triethylamine or pyridine from under ice-coolingto room temperature for 1-24 hours.

The compound of the formula (43) or (44) thus obtained is reduced in asuitable solvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, toluene and mixed solvents of optionalmembers therefrom) using a reducing agent such as lithium aluminumhydride and borane at −78° C. to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (45) or (46).

A compound of the formula (49) obtained by the method described in J.Heterocyclic Chem., vol. 19, p. 1355 (1982) is refluxed under heating ina solvent that does not interfere with the reaction (e.g., methanol,ethanol, propanol, butanol, ethylene glycol and dithylene glycol) in thepresence of hydrazine and a base (e.g., sodium hydroxide and potassiumhydroxide) for 1-24 hours to give a compound of the formula (50). Thisreaction can be also carried out by clemmensen reaction or thioketalmethod to give a compound of the formula (50). This compound is treatedaccording to the method described in Japanese Patent UnexaminedPublication No. 189179/1983 to give a compound of the formula (51). Thiscompound is reacted with a compound of the formula (26) using a fusingagent such as 1,3dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, diethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (52). When a reactivederivative (acid chloride and acylimidazol) of the compound of theformula (51) is used, the reaction proceeds in a suitable solvent thatdoes not interfere with the reaction (e.g., tetrahydrofuran,dichloromethane, chloroform, benzene and mixed solvents of optionalmembers therefrom) in the presence of a tertiary amine such astriethylamine or pyrridine from under ice-cooling to room temperaturefor 1-24 hours.

The compound of the formula (52) thus obtained is reduced in a suitablesolvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, toluene and mixed solvents of optionalmembers therefrom) using a reducing agent such as lithium aluminumhydride and borane at −78° C. to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (53).

A compound of the formula (50) is reacted with a compound of the formula(54), wherein X is chlorine or bromine and other symbols are as definedabove, in a solvent that does not interfere with the reaction (e.g.,methylene chloride, chloroform, methylene dichloride and nitrobenzene)in the presence of a Lewis acid (e.g., aluminum chloride, iron(III)chloride, tin chloride and boron trifluoride) at −78° C. to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (55). This compound is reacted with a compound of theformula (26) or an acid addition salt thereof (e.g., hydrochloride,hydrobromide, sulfate and oxalate) in a suitable solvent that does notinterfere with the reaction (e.g., tetrahydrofuran, dichloromethane,dimethylformamide and mixed solvents of optional members therefrom) inthe presence of a suitable base (e.g., potassium carbonate, pyridine andtriethylamine) at room temperature to the reflowing temperature of thesolvent for 1-24 hours to give a compound of the formula (56). Thiscompound is reacted with a suitable reducing agent (e.g., sodiumborohydride, borane and lithium aluminum hydride) in a solvent that doesnot interfere with the reaction (e.g., methanol, ethanol, propanol,methylene chloride, chloroform, methylene dichloride and mixed solventsof optional members therefrom) to give a compound of the formula (57).

This compound is treated according to the method described in Bull.Chem. Soc. Jpn., vol. 62, p. 3537 (1989) to give a compound of theformula (58). A compound of the formula (56) is refluxed under heatingin a solvent that does not interfere with the reaction (e.g., methanol,ethanol, propanol, butanol, ethylene glycol and diethylene glycol) inthe presence of hydrazine and a base (e.g., sodium hydroxide andpotassium hydroxide) for 1-24 hours to give a compound of the formula(58). This reaction can be also carried out by clemmensen reaction orthioketal method to give a compound of the formula (58).

4. Compound wherein R is a group of the formula (5) or (6):

A compound of the formula (38) is reacted in a suitable solvent (e.g.,methanol, ethanol, butanol, ethylene glycol, methylene chloride,chloroform and mixed solvents of optional members therefrom) in thepresence of hydroxylamine hydrochloride at room temperature to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (I-5) or the formula (I-6).

This compound of the formula (42) is reacted in a suitable solvent(e.g., methanol, ethanol, butanol, ethylene glycol, methylene chloride,chloroform and mixed solvents of optional members therefrom) in thepresence of hydroxylamine hydrochloride at room temperature, to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (59) or (60) or a mixture thereof. In the case of amixture, it can be separated by a purification method such as silica gelcolumn chromatography and recrystallization. The compound of the formula(59) or (60) thus obtained is reduced in a suitable solvent that doesnot interfere with the reaction (e.g., tetrahydrofuran, diethyl ether,toluene and mixed solvents of optional members therefrom) using areducing agent such as aluminum lithium hydride and borane at −78° C. tothe refluxing temperature of the solvent for 1-24 hours to give acompound of the formula (61) or (62).

A compound of the formula (36) is reacted with hydroxylaminehydrochloride under acidic or neutral conditions in a suitable solventthat does not interfere with the reaction (e.g., methanol, ethanol,butanol, ethylene glycol and mixed solvents of optional memberstherefrom) to give a compound of the formula (63). This compound isreacted with a compound of the formula (64) in a suitable solvent thatdoes not interfere with the reaction (e.g., tetrahydrofuran, diethylether and mixed solvents of optional members therefrom) in the presenceof a suitable dehydrogenating agent (e.g., sodium hydride and n-butyllithium) from under ice-cooing to room temperature for 1-24 hours togive a compound of the formula (I-6).

5. Compound wherein R is a group of the formula (7):

A compound of the formula (65) obtained by the method described inChemistry of heterocyclic compounds, vol. 9, p. 920 (1982) is treated bythe method described in Tetrahedron Lett. Vol. 14, p. 1721 (1968) togive a compound of the formula (66). This compound is reacted with acompound of the formula (54) wherein X is chlorine or bromine and othersymbols are as defined above in a solvent that does not interfere withthe reaction (e.g., methylene chloride, chloroform, methylene dichlorideand nitrobenzene) in the presence of a Lewis acid (e.g., chloridealuminum, iron(III) chloride, tin chloride and boron trifluoride) at−78° C. to the refluxing temperature of the solvent for 1-24 hours togive a compound of the formula (67). This compound is reacted with acompound of the formula (26) or an acid addition salt thereof (e.g.,hydrochloride, hydrobromide, sulfate and oxalate) in a suitable solventthat does not interfere with the reaction (e.g., tetrahydrofuran,dichloromethane, dimethylformamide and mixed solvents of optionalmembers therefrom) in the presence of a suitable base (e.g., potassiumcarbonate, pyridine and triethylamine) at room temperature to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (68). This compound is reacted in a two phase solvent ofa suitable solvent that does not interfere with the reaction (e.g.,methylene chloride, chloroform, toluene and 1,4-dioxane) and an aqueoussolution of a suitable base (e.g., sodium hydroxide and potassiumhydroxide) to give a compound of the formula (69).

This compound is reacted with a suitable reducing agent (e.g., sodiumborohydride, borane and lithium aluminum hydride) in a solvent that doesnot interfere with the reaction (e.g., methanol, ethanol, propanol,methylene chloride, chloroform, methylene dichloride and mixed solventsof optional members therefrom) to give a compound of the formula (70).This compound is treated according to the method described in Bull.Chem. Soc. Jpn, vol. 62, p. 3532 (1989) to give a compound of theformula (71). A compound of the formula (69) is refluxed under heatingin a solvent that does not interfere with the reaction (e.g., methanol,ethanol, propanol, butanol, ethylene glycol and dithylene glycol) in thepresence of hydrazine and a base (e.g., sodium hydroxide and potassiumhydroxide) for 1-24 hours to give a compound of the formula (71). Thisreaction can be also carried out by clemmensen reaction or thioketalmethod to give a compound of the formula (71).

The compound thus obtained is reacted with R⁸-L wherein L is as definedabove in a suitable solvent that does not interfere with the reaction(e.g., chloroform, tetrahydrofuran, toluene, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a suitablebase such as triethylamine, potassium carbonate, sodium hydroxide andpotassium tertbutoxide to give the compound of the formula (72).

6. Compound wherein R is a group of the formula (8):

A compound of the formula (73) obtained by the method described inTetrahedron Lett., vol. 30, p. 4625 (1989) is stirred with heating inacetic anhydride in the presence of dimethylamine hydrochloride andformaldehyde for 1-24 hours to give a compound of the formula (74). Thiscompound is reacted with methyl iodide in a suitable solvent (e.g.,methanol, ethanol and acetone) to give a compound of the formula (75).This compound is reacted in a suitable solvent (e.g., methanol, ethanoland propanol) in the presence of a compound of the formula (26) at roomtemperature to the refluxing temperature of the solvent for 1-24 hoursto give a compound of the formula (76). A compound of the formula (73)is stirred with heating in acetic anhydride in the presence ofhydrochloride of a compound of the formula (26) and formaldehyde for1-24 hours to give a compound of the formula (76).

The compound of the formula (76) thus obtained is reacted with asuitable reducing agent such as sodium borohydride, borane and lithiumaluminum hydride in a suitable solvent that does not interfere with thereaction (e.g., methanol, ethanol, propanol, methylene chloride,chloroform, methylene dichloride and mixed solvents of optional memberstherefrom) to give a compound of the formula (77). This compound istreated by the method described in Bull. Chem. Soc. Jpn., vol. 62, p.3537 (1989) to give a compound of the formula (78). A compound of theformula (76) is refluxed under heating in a solvent that does notinterfere with the reaction (e.g., methanol, ethanol, propanol, butanol,ethylene glycol and dithylene glycol) in the presence of hydrazine and abase (e.g., sodium hydroxide and potassium hydroxide) for 1-24 hours togive a compound of the formula (78). This reaction can be also carriedout by clemmensen reaction or thioketal method to give a compound of theformula (78).

7. Compound wherein R is a group of the formula (9):

Using a compound of the formula (79) obtained by the method described inHeterocycles, vol. 31, p. 9 (1990) and in accordance with the methoddescribed in Japanese Patent Unexamined Publication No. 189179/1983, acompound of the formula (80) is obtained. This compound is reacted witha compound of the formula (26) using a fusing agent such as1,3-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and cyanophosphonic aciddiester in a suitable solvent that does not interfere with the reaction(e.g., tetrahydrofuran, dichloromethane, dimethylformamide and mixedsolvents of optional members therefrom) in the presence of a tertiaryamine such as triethylamine from under ice-cooling to room temperaturefor 1-24 hours to give a compound of the formula (81). When a reactivederivative (acid chloride and acylimidazol) of a compound of the formula(80) is used, the reaction proceeds in a suitable solvent that does notinterfere with the reaction (e.g., tetrahydrofuran, dichloromethane,chloroform, benzene and mixed solvents of optional members therefrom) inthe presence of a tertiary amine such as triethylamine or pyridine fromunder ice-cooling to room temperature for 1-24 hours.

The compound of the formula (81) thus obtained is reduced in a suitablesolvent that does not interfere with the reaction (e.g.,tetrahydrofuran, diethyl ether, toluene and mixed solvents of optionalmembers therefrom) using a reducing agent such as lithium aluminumhydride and borane at −78° C. to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (82).

A compound of the formula (79) is reacted with a compound of the formula(54) wherein X is chlorine or bromine and other symbols are as definedabove in a solvent that does not interfere with the reaction (e.g.,methylene chloride, chloroform, methylene dichloride and nitrobenzene)in the presence of a Lewis acid (e.g., aluminum chloride, iron(III)chloride, tin chloride and boron trifluoride) at −78° C. to therefluxing temperature of the solvent for 1-24 hours to give a compoundof the formula (83). This compound is reacted with a compound of theformula (26) or an acid addition salt thereof (e.g., hydrochloride,hydrobromide, sulfate and oxalate) in a suitable solvent that does notinterfere with the reaction (e.g., tetrahydrofuran, dichloromethane,dimethylformamide and mixed solvents of optional members therefrom) inthe presence of a suitable base (e.g., potassium carbonate, pyridine andtriethylamine) at room temperature to the refluxing temperature of thesolvent for 1-24 hours to give a compound of the formula (84). Thiscompound is reacted with a suitable reducing agent (e.g., sodiumborohydride, borane and lithium aluminum hydride) in a solvent that doesnot interfere with the reaction (e.g., methanol, ethanol, propanol,methylene chloride, chloroform, methylene dichloride and mixed solventsof optional members therefrom) to give a compound of the formula (85).This compound is treated according to the method described in Bull.Chem. Soc. Jpn., vol. 62, p. 3537 (1989) to give a compound of theformula (82). A compound of the formula (84) is refluxed under heatingin a solvent that does not interfere with the reaction (e.g., methanol,ethanol, propanol, butanol, ethylene glycol and diethylene glycol) inthe presence of hydrazine and a base (e.g., sodium hydroxide andpotassium hydroxide) for 1-24 hours to give a compound of the formula(82). This reaction can be also carried out by clemmensen reaction orthioketal method to give a compound of the formula (82).

The pharmaceutically acceptable salt of the compound of the formula (I)is exemplified by acid addition salt with inorganic acid or organicacid, which is obtained by treating the compound of the formula (I) withan inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid and nitric acid), or organic acid (e.g., aceticacid, propionic acid, succinic acid, glycolic acid, lactic acid, malicacid, tartaric acid, citric acid, maleic acid, fumaric acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,camphorsulfonic acid and ascorbic acid) by a conventional method. Forcrystallization of the compound, oxalic acid may be added to giveoxalate.

The inventive compound thus obtained can be separated and purified by aconventional method such as recrystallization and column chromatography.When the obtained product is a racemate, the desired optically activecompounds can be obtained by preparative recrystallization from a saltwith an optically active acid or by passing through a column packed withan optically active carrier. Each diastereomer can be separated bypreparative recrystallization, chromatography and the like. These can bealso obtained by the use of an optically active starting material. Inaddition, a stereoisomer can be separated by recrystallization, columnchromatography and the like.

Inasmuch as the fused heterocyclic compound of the present invention, anoptical isomer thereof and a pharmaceutically acceptable salt thereofshow a strong blocking action on D₄receptor and 5-HT₂ receptor, as wellas blockage of NMDA receptor hypofunction, they can be usefulantipsychotic agents that are effective not only for positive symptomscentering on hallucination and delusion characteristic of the acutestage of schizophrenia, but also negative symptoms of apathy, abulia andautism. They are also expected to make antipsychotic agents associatedwith less side effects, such as extrapyramidal symptoms and endocrinedisturbance, which are observed when a conventional antipsychotic agenthaving a D₂ receptor blocking action is administered. Therefore, theinventive compound can be used as a therapeutic agent for the diseasessuch as schizophrenia

When the inventive compound is used as a pharmaceutical agent, theinventive compound is admixed with pharmaceutically acceptable carriers(e.g., excipients, binders, disintegrators, correctives, corrigents,emulsifying agents, diluents and solubilizers) to give a pharmaceuticalcomposition which is then formulated by a conventional method to givetablets, pills, capsules, granules, powders, syrups, emulsions, elixirs,suspensions, solutions, injections, transfusions and suppositories whichcan be administered orally or parenterally.

In the present specification, by parenteral is meant subcutaneousinjection, intravenous injection, intramuscular injection,intraperitoneal injection, transfusion and the like. A preparation forinjection such as sterile aqueous and oily suspensions for injection canbe prepared by a method known in this field using a suitable dispersingagent, wetting agent and suspending agent. The sterile preparation forinjection may be a sterile injectable solution (e.g., aqueous solution)or suspension in a diluent or solvent that is nontoxic and parenterallyadministrable. Examples of usable vehicle and solvent include water,Ringer solution, isotonic brine and the like. In addition, sterilenonvolatile oil can be generally used as a solvent or a suspendingsolvent. Any nonvolatile oil or fatty acid can be used for this end, andexamples thereof include natural, synthetic or semisynthetic lipid oilor fatty acid, and natural, synthetic or semisynthetic mono-, di- ortriglycerides. A suppository for rectal administration can be preparedupon mixing a drug with a suitable nonirritant vehicle, such as cocoabutter and polyethylene glycols, which are solid at normal temperatureand liquid at a temperature of the intestine and which melt in rectum torelease the drug.

The solid dosage form for oral administration may be, for example,powder, granule, tablet, pill or capsule mentioned above. In thesedosage forms, the active compound can be admixed with at least oneadditive, such as sucrose, lactose, cellulose sugar, mannitol, maltitol,dextran, starches, agar, arginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semisynthetic polymers and glycerols. A product having sucha dosage form may further contain different additives as usual, such asinert diluents, lubricants such as magnesium stearate, preservativessuch as sodium p-hydroxybenzoate and sorbic acids, antioxidants such asascorbic acid, α-tocopherol and cysteine, disintegrators, binders,thickeners, buffers, sweeteners, flavors, perfumes and the like. Tabletsand pills may be enteric coated. The liquid preparation for oraladministration is exemplified by pharmaceutically acceptable emulsion,syrup, elixir, suspension, solution and the lie, which may contain aninert diluent normally used in this field, such as water.

The dose is determined in consideration of age, body weight, generalcondition of health, sex, diet, administration time, administrationroute, excretion rate, combination of drugs, disease state being treatedat that time of the patient and other factors. The inventive compound,an optical isomer thereof and a pharmaceutically acceptable salt thereofare low toxic and can be used safely. The daily dose, which is subjectto change according to the condition and body weight of patient, thekind of compound, administration route and the like, is about 0.01-50mg/patient/day, preferably 0.01-20 mg/patient/day, for subcutaneous,intravenous, intramuscular or intraperitoneal administration, and about0.01-150 mg/patient/day, preferably 0.1-100 mg/patient/day, for oraladministration.

The present invention is described in more detail by referring to thestarting material synthesis examples, examples and formulation examples,to which the present invention is not limited.

Starting Material Synthesis Example 1

Hydrazine hydrate (1.1 g) was added to a solution (40 ml) of4-oxo-4-(2-oxocyclohexyl)-n-butyric acid (4.1 g) in ethanol and themixture was refluxed for 1 hour. After the completion of the reaction,the reaction mixture was cooled and the precitated crystals werecollected by filtration to give 3.9 g of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid, m.p. 135-136° C.

Starting Material Synthesis Example 2

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(2-oxocyclohexyl)propionic acid was used as the startingmaterial instead of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid,2-(4,5,6,7-tetrahydro-2H-indazol-3-yl)acetic acid was obtained, m.p.155-156° C.

Starting Material Synthesis Example 3

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(2-oxocyclohexyl)valeric acid was used as a startingmaterial instead of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid,4-(4,5,6,7-tetrahydro-2H-indazol-3-yl)-n-butyric acid was obtained, m.p.94-96° C.

Starting Material Synthesis Example 4

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(2-oxocyclopentyl)-n-butyric acid was used as a startingmaterial instead of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid,3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid was obtained,m.p. 157-159° C.

Staring Material Synthesis Example 5

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(2-oxocycloheptyl)-n-butyric acid was used as a staringmaterial instead of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid,3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid wasobtained, m.p. 102-105° C.

Starting Material Synthesis Example 6

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(4-oxo-2,3,5,6-tetrahydro-4H-pyran-3-yl)-n-butyric acid isused as a starting material instead of4-oxo-4-(2-oxocyclohexyl)-n-butyric acid,3-(2,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)propionic acid isobtained.

Starting Material Synthesis Example 7

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(4-oxo-2,3,5,6-tetrahydro-4H-thiopyran-3-yl)-n-butiric acidis used as a starting material instead of4-4-(2-oxocyclohexyl)-n-butyric acid,3-(2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)propionic acid isobtained.

Staring Material Synthesis Example 8

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-oxo-4-(1-benzoyl-4-oxopiperidin-3-yl)-n-butyric acid was used asa starting material instead of 4-oxo-4-(2-oxocyclohexyl)-n-butyric acid,3-(5-benzoyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-]pyridin-3-yl)propionicacid was obtained, m.p. 143-145° C.

Starting Material Synthesis Example 9

In the same manner as in Starting Material Synthesis Example 1 exceptthat methylhydrazine is used as a starting material instead of hydrazinehydrate, 3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acidis obtained.

Starting Material Synthesis Example 10

In the same manner as in Starting Material Synthesis Example 1 exceptthat 2-pyridylhydrazine is used as a starting material instead ofhydrazine hydrate,3-(4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazol-3-yl)propionic acid isobtained.

Starting Material Synthesis Example 11

In the same manner as in Starting Material Synthesis Example 1 exceptthat phenylhydrazine is used as a starting material instead of hydrazinehydrate, 3-(4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl)propionic acidis obtained.

Starting Material Synthesis Example 12

In the same manner as in Starting Material Synthesis Example 1 exceptthat 4-chlorophenylhydrazine is used as a starting material instead ofhydrazine hydrate,3-(2-(4-chlorophenyl)4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acidis obtained.

Starting Material Synthesis Example 13

4,5,6,7-Tetrahydro-1-methyl-1H-indazole (10 g) and 3-chloropropionylchloride (26 g) were dissolved in dichloroethane (100 ml) and aluminumchloride (28 g) was gradually added under an ice bath while stirring themixture The reaction mixture was stirred for 17 hours at roomtemperature and poured into ice water. The reaction mixture was stirredfor 2 hours at room temperature and extracted twice with chloroform. Thechloroform layer was washed with saturated aqueous sodiumhydrogencarbonate solution and saturated brine and dried over magnesiumsulfate. The magnesium sulfate was filtered off and the solvent wasevaporated under reduced pressure. The obtained residue was subjected tosilica gel column chromatography (silica gel 100 g) and3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole (10 g) wasobtained from an eluate of hexane:ethyl acetate=20:1.

Starting Material Synthesis Example 14

In the same manner as in Starting Material Synthesis Example 13 exceptthat 4,5,6,7-tetrahydro-1-phenyl-1H-indazole is used as a startingmaterial instead of 4,5,6,7-tetrahydro-1-methyl-1H-indazole,3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-phenyl-2H-indazole isobtained.

Starting Material Synthesis Example 15

In the same manner as in Starting Material Synthesis Example 13 exceptthat 1-benzenesulfonyl-4,5,6,7-tetrahydroindole is used as a startingmaterial instead of 4,5,6,7-tetrahydro-1-methyl-1H-indazole,1-benzenesulfonyl-3-(3-chloropropionyl)-4,5,6,7-tetrahydroindole isobtained.

Starting Material Synthesis Example 16

Acetic anhydride (4.3 g) was dropwise added while stirring dimethylaminehydrochloride (1.0 g) and 37% formaldehyde solution (1.0 g) at 50° C.After the dropwise addition, the reaction mixture was stirred at 80° C.for 1 hour, and 3-acetyl-4,5,6,7-tetrahydropyrazolo[2,3-a]pyridine (1.4g) was added. The mixture was stirred for 2 hours with heating. Thereaction mixture was poured into ice water and potassium carbonate wasadded, which was followed by extraction with chloroform. The extract wasdried over magnesium sulfate and the solution was evaporated underreduced pressure to give 1.75 g of3-(3-(N,N-dimethylamino)propionyl)-4,5,6,7-tetrahydropyrazolo[2,3-a]pyridine.This compound (1.75 g) was dissolved in acetone (10 ml) and methyliodide (1.1 g) was added. The precipitated crystals were collected byfiltration to give 1.2 g of a quaternary salt of(3-(4,5,6,7-tetrahydropyrazolo[2,3-a]pyridin-3-yl)-3-oxypropyl)trimethylammoniumiodide, m.p. 210-213° C.

Starting Material Synthesis Example 17

In the same manner as in Starting Material Synthesis Example 13 exceptthat 5,6,7,8-tetrahydroindolizine is used as a staring material insteadof 4,5,6,7-tetrahydro-1-methyl-1H-indazole,3-(3-chloropropionyl)-5,6,7,8-tetrahydroindolizine is obtained.

EXAMPLE 1

To a solution (30 ml) of 1-aza-2-methylthio-1-cycloheptene (1.43 g) inbutanol was added3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide (3.12g) with stirring, and the mixture was refluxed under heating for 3hours. After the completion of the reaction, the solvent was evaporatedunder reduced pressure, and the obtained residue was recrystallized fromisopropyl alcohol to give 0.1 g of3-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine,m.p. 163° C.

EXAMPLE 2

To a solution (30 ml) of 1-aza-2-methylthio-1-cycloheptene (1.43 g) inbutanol was added3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide(3.13 g) with stirring, and the mixture was refluxed under heating for 3hours. After the completion of the reaction, the solvent was evaporatedunder reduced pressure, and the obtained residue was dissolved inisopropyl alcohol and maleic acid was added to form a salt. The salt wascollected by filtration and recrystallized from ethanol to give 4.2 g of3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedimaleate, m.p. 186° C.

EXAMPLE 3

3-(3-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine(1 g) obtained in Example 1 was added to a solution (20 ml) of sodiumiodide (2.76 g) and trimethylsilyl chloride (2 g) in acetonitrile withstirring, and the mix was refluxed under heating for 3 hours. After thecompletion of the reaction, the solvent was evaporated under reducedpressure, and the obtained residue was dissolved in isopropyl alcohol. Asolution of hydrogen chloride in isopropyl alcohol was added to form ahydrochloride thereof, which was collected by filtration andrecrystallized from ethanol to give 0.1 g of3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedihydrochloride, m.p. not less than 250° C.

EXAMPLE 4

To a solution (150 ml) of 1-aza-2-methoxy-1-cycloheptene (23.6 g) inbutanol was added 3-hydroxypropylcarbohydrazide (23 g) with stirring,and the mixture was refluxed under heating for 3 hours. After thecompletion of the reaction, the solvent was evaporated under reducedpressure, and the obtained residue was subjected to silica gel columnchromatography to give 29 g of3-(3-hydroxypropyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine.To a solution of this compound (0.98 g) in dimethylformamide (20 ml)were added triethylamine (1.4 ml) and methanesulfonyl chloride (0.62 ml)with stirring. Then, 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (1.28g), potassium carbonate (1.38 g) and potassium iodide (0.83 g) wereadded and the mixture was stirred for 4 hours at 60° C. After thecompletion of the reaction, the reaction mixture was poured into water,extracted with ethyl acetate, washed with water, and dried overmagnesium sulfate. The solution was concentrated under reduced pressureto give3-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine.

For crystallization, the obtained compound was dissolved in isopropylalcohol and oxalic acid was added thereto to form a salt thereof, whichwas collected by filtration and recrystallized from ethanol to give 0.38g of3-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedioxalate, m.p. 151-153° C.

EXAMPLE 5

Triethylamine (1.4 ml) and methanesulfonyl chloride (0.62 ml) were addedto a solution of3-(3-hydroxypropyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine(0.98 g) obtained in the same manner as in Example 4 indimethylformamide (20 ml) with stirring. Then, ⁴-benzylpiperidine (0.88g), potassium carbonate (1.38 g) and potassium iodide (0.83 g) wereadded and the mixture was stirred for 4 hours at 60° C. After thecompletion of the reaction, the reaction mixture was poured into water,extracted with ethyl acetate, washed with water, and dried overmagnesium sulfate. The solution was concentrated under reduced pressureto give3-(3-(4-benzylpiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine.

For crystallization, the obtained compound was dissolved in isopropylalcohol and oxalic acid was added thereto to form a salt thereof, whichwas collected by filtration and recrystallized from ethanol to give 0.15g of3-(3-(4-benzylpiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedioxalate, m.p. 156-158° C.

EXAMPLE 6

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-chlorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 7

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(3-chlorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(3-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained, m.p. 146-148° C.

EXAMPLE 8

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-bromophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 9

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 10

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-hydroxy-4-(4-methylphenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-hydroxy-4-(4-methylphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained, m.p. 160-161° C.

EXAMPLE 11

To a solution (30 ml) of 1-aza-2-methoxy-1-cycloheptene (2.31 g) inbutanol was added3-(4-(4-chloro-3-trifluoromethylphenyl)-1-hydroxypiperidin-1-yl)propylcarbohydrazide(3.5 g) with stirring, and the mixture was refluxed under heating for 3hours. After the completion of the reaction, the solvent was evaporatedunder reduced pressure, and the obtained residue was recrystallized froma mixed solvent of ethyl alcohol and ethyl acetate to give 2.8 g of3-(3-(4-(4-chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine,m.p. 151° C.

EXAMPLE 12

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-2-methylphenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-2-methylphenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 13

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2,3-dichlorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2,3-dichlorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 14

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-hydroxy-4-(1-naphthyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-hydroxy-4-(1-naphthyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 15

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-hydroxy-4-(2-naphthyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-hydroxy-4-(2-naphthyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 16

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-chloro-5-trifluoromethylphenyl)4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2-chloro-5-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 17

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-2-fluorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 18

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-3-fluorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-3-fluorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 19

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(3-chloro-4-fluorophenyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide,3-(3-(4-(3-chloro-4-fluorophenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 20

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-chlorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 21

By the same reaction and treatment as in Example 1using-1-aza-2-methoxy-1-cycloheptene and3-(4-(3-chlorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(3-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 22

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-bromophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-bromophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 23

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-methoxyphenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-methoxyphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4triazolo[4,3-a]azepineis obtained.

EXAMPLE 24

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-methylphenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-methylphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 25

To a solution of sodium iodide (0.43 g) and trimethylsilyl chloride(0.32 g) in acetonitrile (40 ml) was added3-(3-(4-(4-chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine(0.22 g) obtained in Example 11 with stirring, and the mixture wasrefluxed under heating for 3 hours. After the completion of thereaction, the solvent was evaporated under reduced pressure, and theobtained residue was dissolved in isopropyl alcohol. Thereto was added asolution of hydrogen chloride in isopropyl alcohol to form ahydrochloride thereof, which was collected by filtration andrecrystallized from ethanol to give 0.05 g of3-(3-(4-(4-chloro-3-trifluoromethylphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine dihydrochloride 3/2 hydrate, m.p. 255° C.(decomposition).

EXAMPLE 26

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 27

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2,3-dichlorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2,3-dichlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 28

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(1-naphthyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(1-naphthyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 29

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-naphthyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2-naphthyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 30

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-chloro-5-trifluoromethylphenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(2-chloro-5-trifluoromethylphenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 31

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 32

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 33

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 34

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(2-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 35

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazideand then by a conventional treatment using maleic acid,3-(3-(4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedimaleate was obtained, m.p. 173-174° C.

EXAMPLE 36

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-bromophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-bromophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained.

¹H-NMR(CDCl₃)δ: 1.62-1.80(4H,m), 1.81-1.92(2H,m), 2.01(2H,tt,J=7.7 Hz),2.43-2.62(4H,m), 2.70(2H,t,J=6 Hz), 2.81(2H,t,J=7 Hz), 2.96(2H,t,J=6Hz), 3.10-3.19(2H,m), 3.89(2H,t,J=5 Hz), 6.02-6.13(1H,m), 7.24(2H,d,J=9Hz), 7.42(2H,d,J=9 Hz)

EXAMPLE 37

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained.

¹H-NMR(CDCl₃)δ: 1.66-1.81(4H,m), 1.82-1.95(2H,m), 2.01(2H,tt,J=8.7 Hz),2.41-2.53(2H,m), 2.56(2H,t,J=7 Hz), 2.69(2H,t,J=6 Hz), 2.79(2H,t,J=8Hz), 2.96(2H,t,J=6 Hz), 3.08-3.18(2H,m), 3.81(3H,s), 3.90(2H,t,J=5 Hz),5.92-6.01(1H,m), 6.85(2H,d,J=9 Hz), 7.32(2H,d,J=9 Hz)

EXAMPLE 38

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained, m.p. 93-96° C.

EXAMPLE 39

To3-(3-(4-(4-chloro-3-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine(0.22 g) obtained in Example 11 were added water (2 ml) and conc.sulfuric acid (11 ml) and the mixture was stirred at 90° C. for 30minutes with heating. After the completion of the reaction, the reactionmixture was made alkaline, extracted with chloroform, washed with water,and dried over magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was dissolved in isopropylalcohol. Thereto was added a solution of hydrogen chloride in isopropylalcohol to form a hydrochloride thereof, which was collected byfiltration and recrystallized from ethanol to give 0.15 g of3-(3-(4-(4-chloro-3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedihydrochloride 1/2 hydrate, m.p. 278° C. (decomposition).

EXAMPLE 40

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-chloro-2-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-2-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained.

¹H-NMR(CDCl₃)δ: 1.65-1.83(4H,m), 1.85-1.93(2H,m), 2.02(2H,tt,J=7.6 Hz),2.26(3H,s), 2.30-2.41(2H,m), 2.59(2H,t,J=7 Hz), 2.70(2H,t,J=5 Hz),2.79(2H,t,J=7 Hz), 2.97(2H,t,J=6 Hz), 3.09-3.21(2H,m), 3.91(2H,t,J=5Hz), 5.49-5.55(1H,m), 7.01(1H,d,J=8 Hz), 7.09(1H,d,J=2 Hz),7.15(1H,dd,J=8.2 Hz)

EXAMPLE 41

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained.

¹H-NMR(CDCl₃)δ: 1.60-1.82(4H,m), 1.83-1.92(2H,m), 2.02(2H,tt,J=8.7 Hz),2.40-2.50(2H,m), 2.58(2H,t,J=7 Hz), 2.70(2H,t,J=5 Hz), 2.80(2H,t,J=8Hz), 2.97(2H,t,J=6 Hz), 3.11-3.18(2H,m), 3.93(2H,t,J=5 Hz),5.61-5.68(1H,m), 7.10(1H,d,J=2 Hz), 7.15(1H,d,J=8 Hz), 7.36(1H,dd,J=8.2Hz)

EXAMPLE 42

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(1-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(1-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 43

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinewas obtained.

¹H-NMR(CDCl₃)δ: 1.62-1.83(4H,m), 1.84-1.94(2H,m), 2.05(2H,tt,J=8.7 Hz),2.61(2H,t,J=7 Hz), 2.67-2.86(6H,m), 2.96(2H,t,J=6 Hz), 3.17-3.26(2H,m),3.91(2H,t,J=5 Hz), 6.20-6.29(1H,m), 7.39-7.50(3H,m), 7.57-7.63(1H,m),7.72-7.85(4H,m)

EXAMPLE 44

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-chloro-5-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(2-chloro-5-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 45

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and 3-(4-(4chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 46

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 47

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 48

To a solution (8 ml) of cycloheptanone oxime (1.2 g) in tetrahydrofuranwas added n-butyllithium (6 ml) under ice-cooling, and ethyl4-(4-(4-chlorophenyl)piperazin-1-yl)-n-butyrate (1 g) was added, whichwas followed by stirring at room temperature for 1-24 hours. After thecompletion of the reaction, the solvent was evaporated under reducedpressure, and the obtained residue was dissolved in isopropyl alcohol.Then, a solution of hydrogen chloride in isopropyl alcohol to form ahydrochloride thereof, which was collected by filtration andrecrystallized from ethanol to give 0.2 g of3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazolehydrochloride, m.p. 220° C. (decomposition).

EXAMPLE 49

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(2-chlorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(2-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 50

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(3-chlorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(3-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 51

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(4-bromophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-bromophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 52

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(4-methoxyphenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-methoxyphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 53

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(4-methylphenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-methylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 54

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-3-trifluoromethylphenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-3-trifluoromethylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 55

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-2-methylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 56

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(2,3-dichlorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(2,3-dichlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 57

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(1-naphthyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(1-naphthyl)piperidin-1-yl)propyl-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 58

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(2-naphthyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(2-naphthyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 59

By the same reaction and treatment as in Example 48 using cycloheptanoneoxide and ethyl4-(4-(2-chloro-5-trifluoromethylphenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(2-chloro-5-trifluoromethylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 60

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 61

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-3-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 62

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(3-chloro-4-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 63

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(2-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(2-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 64

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl-n-butyrate,3-(3-(4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 65

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-bromophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-bromophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 66

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 67

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 68

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butylate,3-(3-(4-(4-chloro-3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 69

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-2-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-2-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydropyridin-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 70

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(2,3-dichlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 71

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(1-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butylate,3-(3-(4-(1-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 72

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(2-naphthyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 73

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(2-chloro-5-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butylate,3-(3-(4-(2-chloro-5-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 74

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 75

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-chloro-3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 76

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 77

By the same reaction and treatment as in Example 1 using5-methoxy-2,3,6,7-tetrahydro[1,4]oxazepine and3-(4-(4-chlorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,8,9-tetrahydro-1,2,4-triazolo[4,3-d][1,4]oxazepineis obtained.

EXAMPLE 78

By the same reaction and treatment as in Example 1 using5-methoxy-2,3,6,7-tetrahydro[1,4]oxazepine and3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,8,9-tetrahydro-1,2,4-triazolo[4,3-d][1,4]oxazepineis obtained.

EXAMPLE 79

By the same reaction and treatment as in Example 1 using5-methoxy-2,3,6,7-tetrahydro[1,4]thiazine and3-(4-(4-chlorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,8,9-tetrahydro-1,2,4-triazolo[4,3-d][1,4]thiazineis obtained.

EXAMPLE 80

By the same reaction and treatment as in Example 1 using5-methoxy-2,3,6,7-tetrahydro[1,4]thiazine and3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,8,9-tetrahydro-1,2,4-triazolo[4,3-d][1,4]thiazineis obtained.

EXAMPLE 81

By the same reaction and treatment as in Example 48 using cyclohexanoneoxime and ethyl 4-(4-(4-chlorophenyl)piperazin-1-yl)-n-butylate,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxaoleis obtained.

EXAMPLE 82

By the same reaction and treatment as in Example 48 usingtetrahydro-4H-pyran-4-one oxime and ethyl4-(4-(4-chlorophenyl)piperazin-1-yl)-n-butylate,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-pyrano[4,3-c]isoxazoleis obtained.

EXAMPLE 83

By the same reaction and treatment as in Example 48 usingtetrahydro-4H-thiopyran-4-one oxime and ethyl4-(4-(4-chlorophenyl)piperazin-1-yl)-n-butyrate,3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-thiopyrano[4,3-c]isoxazoleis obtained.

EXAMPLE 84

To a solution (30 ml) of 1-aza-2-methylthio-1-cycloheptene (5.74 g) inbutanol was added3-(4-(2-thienyl)-4-hydroxypiperidin-1-yl)propylcarbohydrazide (8.5 g)with stirring, and the mixture was refluxed under heating for 3 hours.After the completion of the reaction, the solvent was evaporated underreduced pressure, and the obtained residue was recrystallized from ethylacetate to give 10 g of3-(3-(4-(2-thienyl)-4-hydroxypiperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepine,m.p. 162-163° C.

EXAMPLE 85

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-thienyl)piperidin-1-yl)propylcarbohydmazide,3-(3-(4-(2-thienyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 86

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(2-thienyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide andthen by a conventional treatment using maleic acid,3-(3-(4-(2-thienyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinedimaleate was obtained, m.p. 166-167° C.

EXAMPLE 87

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(5-chloro-2-thienyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(5-chloro-2-thienyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 88

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(5-chloro-2-thienyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(5-chloro-2-thienyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 89

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(4-chlorophenyl)piperidin-1-yl)-n-butyrate,3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 90

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 91

To a solution of 6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine inacetonitrile are added aqueous formaldehyde solution and2,2-dimethyl-1,3-dioxane-4,6-dione with stirring and the mixture isheated for 4 hours. After the completion of the reaction, the reactionmixture is poured into water and the mixture is extracted withchloroform, washed with water, and dried over magnesium sulfate. Thesolution is concentrated under reduced pressure and the resulting2,2-dimethyl-5-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-ylmethyl)-1,3-dioxane-4,6-dioneis dissolved in pyridine with sting. Water and copper powder are addedand the mixture is refluxed under heating for 3 hours. After thecompletion of the reaction, the reaction mixture is filtered while it ishot and the solvent is evaporated under reduced pressure to give3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propionic acid. To asolution of this compound in dimethylformamide are added4-(4-chlorophenyl)piperidine, triethylamine and cyanophosphonic aciddiester and the mixture is stirred at room temperature. After thecompletion of the reaction, the reaction mixture is poured into waterand the mixture is extracted with chloroform, washed with water, anddried over magnesium sulfate. The solution is concentrated under reducedpressure and the resulting1-(4-(4-chlorophenyl)piperidin-1-yl)-3-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)propan-1-oneis dissolved in tetrahydrofuran and lithium aluminum hydride is addedunder ice-cooling with stirring and the mixture is stirred at roomtemperature for 1 hour. After the completion of the reaction, thereaction mixture is poured into water and the mixture is extracted withchloroform, washed with water, and dried over magnesium sulfate. Thesolution is concentrated under reduced pressure and the obtained residueis subjected to silica gel column chromatography to give3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine.

EXAMPLE 92

By the same reaction and treatment as in Example 91 using6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine,2,2-dimethyl-1,3-dioxane-4,6-dione and4-(4chlorophenyl)-1,2,3,6-tetrahydropyridine,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepineis obtained.

EXAMPLE 93

By the same reaction and treatment as in Example 91 using6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine,2,2-dimethyl-1,3-dioxane-4,6-dione and 1-(4-chlorophenyl)piperazine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepineis obtained.

EXAMPLE 94

To a solution of 1-morpholino-1-cycloheptene in chloroform are addedtriethylamine and 4-(4-(4-chlorophenyl)piperidin-1-yl)butanoyl chloridewith stirring and the mixture is stirred at room temperature. After thecompletion of the reaction, the reaction mixture is poured into waterand extracted with chloroform, and the extract is washed with water anddried over magnesium sulfate. The solution is concentrated under reducedpressure. To a mixed solution of the obtained2-(4-(4-(4-chlorophenyl)piperidin-1-yl)butanoyl)cycloheptanone inchloroform and methanol is added hydrazine monohydrate with stirring andthe mixture is stirred at room temperature for 6 hours. After thecompletion of the reaction, the reaction mixed is poured into water andthe mixture is extracted with chloroform, washed with water and driedover magnesium sulfate. The solution is concentrated under reducedpressure and the obtained residue is subjected to silica gel columnchromatography to give3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapymzole.

EXAMPLE 95

By the same reaction and treatment as in Example 94 using1-morpholino-1-cycloheptene and4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)butanoyl chloride,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapymzoleis obtained.

EXAMPLE 96

By the same reaction and treatment as in Example 94 using1-morpholino-1-cycloheptene and4-(4-(4-chlorophenyl)piperazin-1-yl)butanoyl chloride,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapymzoleis obtained.

EXAMPLE 97

By the same reaction and treatment as in Example 48 using cyclohexanoneoxime and ethyl 4-(4-(4-chlorophenyl)piperidin-1-yl)-n-butylate,3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazoleis obtained.

EXAMPLE 98

By the same reaction and treatment as m Example 48 using cyclohexanoneoxime and ethyl4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazoleis obtained.

EXAMPLE 99

To a solution of 3-(imidazo[1,2-a]pyridin-3-yl)propionic acid (4 g)synthesized according to the method described in Japanese PatentUnexamined Publication No. 189179/1983, 1-(4-chlorophenyl)piperazinehydrochloride (4.9 g) and triethylamine (5.9 ml) in dimethylformamidewas added dropwise diethyl cyanophosphate (3.8 ml) under ice-coolingwith stirring, and the mixture was stirred for 3 hours. After thecompletion of the reaction, the reaction mixture was concentrated,extracted with chloroform, washed with water and dyed over magnesiumsulfate. The solution was concentrated under reduced pressure, andlithium aluminum hydride was added to a solution of the obtained4-(4-chlorophenyl)-1-(3-(imidazo[1,2-a]pyridin-3-yl)propionyl)piperazinein tetrahydrofuran under ice-cooling with stirring, and the mixture wasstirred at room temperature for 1 hour. After the completion of thereaction, the reaction mixture was treated with a mixed solvent ofwater-tetrahydrofuran and filtered through celite. The filtrate wasconcentrated under reduced pressure the obtained residue was subjectedto silica gel column chromatography to give3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)imidazo[1,2-a]pyridine.This compound was dissolved in a mixture of ethanol (20 ml) and conc.hydrochloric acid (20 ml) and reduced in the presence of 10%palladium-carbon (1 g) in an autoclave at 70° C. and 50 atm. After thecompletion of the reaction, the reaction mixture was filtered throughcelite. The filtrate was concentrated under reduced pressure and theobtained residue was subjected to silica gel column chromatography togive3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine,m.p. 95-97° C. (m.p. as oxalate).

EXAMPLE 100

In the same manner as in Example 99 except that4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine is used instead of1-(4-chlorophenyl)piperazine,3-(3-(4-(4chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridineis obtained.

EXAMPLE 101

In the same manner as in Example 99 except that4-(4-chlorophenyl)piperidine is used instead of 1-(4chlorophenyl)piperazine,3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridineis obtained.

EXAMPLE 102

To a solution of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid(0.7 g) obtained in Starting Material Synthesis Example1,4-(4-chlorophenyl)piperidine (0.7 g) and triethylamine (1.7 ml) indimethylformamide (10 ml) was added dropwise diethyl cyanophosphate (0.7ml) with stirring, and the mixture was stirred for 3 hours. After thecompletion of the reaction, the reaction mixture was concentrated,extracted with chloroform, washed with water, and dried over magnesiumsulfate. The solution was concentrated under reduced pressure, andlithium aluminum hydride was added to a solution of the obtained4-(4-chlorophenyl)-1-(3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionyl)piperidinein tetrahydrofuran under ice-cooling with stirring, which was followedby stirring at room temperature for 1 hour. After the completion of thereaction, the reaction mixture is treated with a mixed solvent ofwater-tetrahydrofuran and filtered through celite. The filtrate isconcentrated under reduced pressure, the obtained residue is subjectedto silica gel column chromatography to give3-(3-(4-(4-chlorophenyl)piperidin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole.

EXAMPLE 103

In the same manner as in Example 102 using4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.67-1.85(4H,m), 1.89(2H,tt,J=6.7 Hz), 2.35-2.47(2H,m),2.52(2H,t,J=7 Hz), 2.53-2.71(6H,m), 2.71(2H,t,J=6 Hz), 3.12-3.22(2H,m),7.21-7.36(4H,m)

EXAMPLE 104

In the same manner as in Example 102 using 1-(4-chlorophenyl)piperazineinstead of 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole1/10 hydrate was obtained, m.p. 109-111° C.

EXAMPLE 105

By the same reaction and treatment as in Example 48 using cyclohexanoneoxime and ethyl 4-(4-(4-methylphenyl)piperazin-1-yl)-n-butyrate,3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazoleis obtained.

EXAMPLE 106

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 5-(4-(4-fluorophenyl)piperazin-1-yl)-n-valerate and thenby a conventional treatment using hydrochloric acid,3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazolehydrochloride was obtained, m.p. 174-175° C.

EXAMPLE 107

By the same reaction and treatment as in Example 48 usingtetrahydro-4H-pyran-4-one oxime and ethyl4-(4-(4-fluorophenyl)piperazin-1-yl)-n-butyrate,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-6,7-dihydro-4H-pyrano[4,3-c]isoxazoleis obtained.

EXAMPLE 108

By the same reaction and treatment as in Example 48 using cycloheptanoneoxime and ethyl 4-(4-(4-fluorophenyl)piperazin-1-yl)-n-butyrate,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazoleis obtained.

EXAMPLE 109

By the same reaction and treatment as in Example 91 using6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine,2,2-dimethyl-1,3-dioxane-4,6-dione and 1-(4-fluorophenyl)piperazine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepineis obtained.

EXAMPLE 110

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propylcarbohydrazide,3-(3-(4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 111

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and3-(4-(4-fluorophenyl)piperidin-1-yl)propylcarbohydrazide,3-(3-(4-(4-fluorophenyl)piperidin-1-yl)propyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepineis obtained.

EXAMPLE 112

By the same reaction and treatment as in Example 1 using1-aza-2-methoxy-1-cycloheptene and2-(4-(5-methylbenzo[b]furan-3-yl)piperidin-1-yl)ethylcarbohydrazide andthen by a conventional treatment using hydrochloric acid,3-(2-(4-(5-methylbenzo[b]furan-3-yl)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-5H-1,2,4-triazolo[4,3-a]azepinehydrochloride was obtained, m.p. 226° C. (decomposition).

EXAMPLE 113

In the same manner as in Example 99 except that1-(4-fluorophenyl)piperazine was used instead of1-(4-chlorophenyl)piperazine,3-(3-(4-(4-fluorophenyl)piperazine-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridinewas obtained, m.p. 106-108° C.

EXAMPLE 114

In the same manner as in Example 99 except that1-(4-methylphenyl)piperazine is used instead of1-(4-chlorophenyl)piperazine,3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridineis obtained.

EXAMPLE 115

In the same manner as in Example 99 except that 1-phenylpiperazine isused instead of 1-(4-chlorophenyl)piperazine,3-(3-(4-phenylpiperazin-1-yl)propyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridineis obtained.

EXAMPLE 116

In the same manner as in Example 102 except that1-(4-fluorophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained, m.p. 106-108° C. The compound was converted to an acidaddition salt of maleic acid to give3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolemaleate, m.p. 141-142° C. The compound was converted to an acid additionsalt of hydrochloric acid to give3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolehydrochloride, m.p. 210-211 ° C.

EXAMPLE 117

In the same manner as in Example 102 except that1-(4-methylphenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine and then by a conventional treatment usingmaleic acid,3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolemaleate was obtained, m.p. 144-146° C.

EXAMPLE 118

In the same manner as in Example 102 except that 1-phenylpiperazne wasused instead of 4-(4-chlorophenyl)piperidine,3-(3-(4-phenylpiperazin-1-yl)propyl)4,5,6,7-tetrahydro-2H-indazole wasobtained, m.p. 92-94° C. The compound was converted to an acid additionsalt of maleic acid to give3-(3-(4-phenylpiperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolemaleate, m.p. 123-125° C.

EXAMPLE 119

In the same manner as in Example 102 except that1-(4-bromophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(4-bromophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole1/4 hydrate was obtained, m.p. 145-147° C.

EXAMPLE 120

In the same manner as in Example 102 except that1-(3-trifluoromethyl-phenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4(3-trifluoromethylphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.94(6H,m), 2.36-2.53(4H,m), 2.58-2.74(8H,m),3.27(4H,t,J=5 Hz), 7.01-7.17(3H,m), 7.33(1H,t,J=8 Hz)

EXAMPLE 121

In the same manner as in Example 102 except that1-(2-chlorophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(2-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.66-1.92(6H,m), 2.32-2.45(4H,m), 2.55-2.65(8H,m),3.12-3.20(4H,m), 6.98(1H,dt,J=1.8 Hz), 7.07(1H,dd,J=2.8 Hz),7.21(1H,dt,J=1.8 Hz), 7.34(1H,dd,J=1.8 Hz)

EXAMPLE 122

In the same manner as in Example 102 except that1-(2,5-dichlorophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(2,5-dichlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.65-1.90(6H,m), 2.32-2.44(4H,m), 2.52-2.73(8H,m),3.08-3.22(4H,m), 6.95(1H,dd,J=2.9 Hz), 7.02(1H,d,J=3 Hz), 7.25(1H,d,J=9Hz)

EXAMPLE 123

In the same manner as in Example 102 except that1-(3-chlorophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.94(6H,m), 2.38-2.55(4H,m), 2.58-2.65(8H,m),3.23-3.27(4H,m), 6.79(1H,dt,J=2.8 Hz), 6.87(1H,d,J=2 Hz), 7.15(1H,t,J=8Hz)

EXAMPLE 124

In the same manner as in Example 102 except that1-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.75-1.92(10H,m), 2.41-2.52(4H,m), 2.62-2.78(12H,m),2.94-2.97(4H,m), 6.83(1H,d,J=7 Hz), 6.89(1H,d,J=7 Hz), 7.08(1H,t,J=8 Hz)

EXAMPLE 125

In the same manner as in Example 102 except that1-(3,4-dichlorophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(3,4-dichlorophenyl)piperazine-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.94(6H,m), 2.33-2.51(4H,m), 2.53-2.70(8H,m),3.19(4H,t,J=5 Hz), 6.72(1H,dd,J=3.9 Hz), 6.94(1H,d,J=3 Hz),7.25(1H,d,J=9 Hz)

EXAMPLE 126

In the same manner as in Example 102 except that1-(2-methoxyphenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.90(6H,m), 2.38-2.50(4H,m), 2.55-2.68(8H,m),3.19-3.25(4H,m), 3.86(3H,s), 6.84-7.04(4H,m)

EXAMPLE 127

In the same manner as in Example 102 except that1-(2-naphthyl)piperazine obtained in Starting Material Synthesis Example2 was used instead of 4-(4-chlorophenyl)piperidine,3-(3-(4-(2-naphthyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.73-2.10(6H,m), 2.41-2.52(4H,m), 2.55-2.70(8H,m),3.10-3.25(4H,m), 7.13(1H,d,J=2 Hz), 7.24-7.31(2H,m), 7.37-7.42(1H,m),7.73(3H,t,J=8 Hz)

EXAMPLE 128

In the same manner as in Example 102 except that1-(3-methoxyphenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(3-methoxyphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.70-1.91(6H,m), 2.40-2.48(4H,m),2.59-2.66(8H,m),3.21-3.26(4H,m), 3.78(3H,s), 6.41(1H,dd,J=2 Hz, 8 Hz),6.46(1H,t,J=2 Hz), 6.53(1H,dd,J=2 Hz, 8 Hz), 7.16(1H,t,J=8 Hz)

EXAMPLE 129

In the same manner as in Example 102 except that4-(6-fluoro-1,2-benzoisoxazol-3-yl)piperidine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(6-fluoro-1,2-benzoisoxazol-3-yl)piperidin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolemonohydrate was obtained, m.p. 124-126° C.

EXAMPLE 130

In the same manner as in Example 102 except that1-(1-naphthyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(1-naphthyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDC₃)δ: 1.65-1.91(6H,m), 2.35-2.52(4H,m), 2.55-2.70(8H,m),3.00-3.12(4H,m), 7.14(1H,d,J=7 Hz), 7.40(1H,t,J=8 Hz), 7.45-7.50(2H,m),7.58(1H,d,J=8 Hz), 7.81-7.85(1H,m), 8.12-8.15(1H,m)

EXAMPLE 131

In the same manner as in Example 102 except that1-(5-methylbenzo-[b]furan-3-yl)piperidine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(5-methylbenzo[b]furan-3-yl)piperidin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.70-1.98(6H,m), 2.04-2.39(6H,m), 2.36-2.55(4H,m),2.45(3H,s), 2.58-2.72(4H,m), 3.01-3.22(3H,m), 7.12(1H,d,J=9 Hz),7.42(1H,d,J=9 Hz), 7.54(1H,s), 7.78(1H,s)

EXAMPLE 132

In the same manner as in Example 102 except that2-(4,5,6,7-tetrahydro-2H-indazol-3-yl)acetic acid obtained in StartingMaterial Synthesis Example 2 and 1-(4-fluorophenyl)piperazine were usedinstead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtainedin Staring Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,3-(2-(4-(4-fluorophenyl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2H-indazoleis obtained.

EXAMPLE 133

In the same manner as in Example 102 except that4-(4,5,6,7-tetrahydro-2H-indazol-3-yl)-n-butyric acid obtained inStarting Material Synthesis Example 3 and 1-(4-fluorophenyl)piperazinewere used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionicacid obtained in Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.52-1.83(8H,m), 2.35-2.44(4H,m), 2.57-2.65(8H,m),3.11-3.15(4H,m), 6.83-6.99(4H,m)

EXAMPLE 134

In the same manner as in Example 102 except that3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 4 and 1-(4-fluorophenyl)piperazinewere used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionicacid obtained in Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine and then by a conventional treatment usinghydrochloric acid,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazoledihydrochloride dihydrate was obtained, m.p. 228-230° C.

EXAMPLE 135

In the same manner as in Example 102 except that3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 4 and 1-(4-methylphenyl)piperazinewere used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionicacid obtained in Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazolewas obtained, m.p. 101-102° C.

EXAMPLE 136

In the same manner as in Example 102 except that3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 5 and1-(4-fluorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.57-1.70(4H,m), 1.77-1.87(4H,m), 2.43-2.48(4H,m),2.61-2.66(6H,m), 2.70-2.75(2H,m), 3.14-3.18(4H,m), 6.84-7.00(4H,m)

EXAMPLE 137

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 6 and1-(4-fluorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4 halophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.85(2H,tt,J=6.6 Hz), 2.48(2H,t,J=7 Hz),2.57-2.71(6H,m), 2.78(2H,t,J=6 Hz), 3.18(4H,t,J=5 Hz), 3.93(2H,t,J=6Hz), 4.65(2H,s), 6.82-7.01(4H,m)

EXAMPLE 138

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 7 and1-(4-fluorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazolewas obtained, m.p. 110-111° C.

EXAMPLE 139

In the same manner as in Example 102 except that3-(5-benzoyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)propionicacid obtained in Starting Material Synthesis Example 8 and1-(4-fluorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,5-benzyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinewas obtained.

¹H-NMR(CDCl₃)δ: 1.82(2H,tt,J=7.7 Hz), 2.46(2H,t,J=7 Hz),2.55-2.67(6H,m), 2.77(4H,s), 3.12-3.20(4H,m), 3.44(2H,s), 3.72(2H,s),6.82-6.98(4H,m), 7.21-7.40(5H,m)

EXAMPLE 140

In the same manner as in Example 102 except that3-(5-benzoyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)propionicacid obtained in Starting Material Synthesis Example 8 and1-(4-chlorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in StatingMaterial Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,5-benzyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinewas obtained.

¹H-NMR(CDCl₃)δ: 1.82(2H,tt,J=7.7 Hz), 2.45(2H,t,J=7 Hz),2.52-2.66(6H,m), 2.76(4H,s), 3.14-3.24(4H,m), 3.43(2H,s), 3.72(2H,s),6.84(2H,t,J=9 Hz), 7.19(2H,t,J=9 Hz), 7.21-7.40(5H,m)

EXAMPLE 141

5-Benzyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(0.5 g) obtained in Example 139 was dissolved in ethanol (10 ml), andRaney nickel (0.2 g) was added to perform catalytic reduction. After thecompletion of the reaction, the reaction mixture was filtered throughcelite and the filtrate was concentrated under reduced pressure. Theobtained residue was subjected to silica gel column chromatography togive3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,

¹H-NMR(CDCl₃)δ: 1.86(2H,tt,J=7.6 Hz), 2.45(2H,t,J=7 Hz),2.55-2.66(4H,m), 2.89(2H,t,J=6 Hz), 3.00-3.14(6H,m), 3.16-3.23(2H,m),3.76(2H,s), 6.81-6.98(4H,m)

EXAMPLE 142

3-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(0.3 g) obtained in Example 141 was dissolved in a mixed solution ofchloroform (5 ml) and saturated aqueous sodium hydrogencarbonatesolution (5 ml), and acetyl chloride (0.3 ml) was added dropwise underice-cooling. After the dropwise addition, the chloroform layer waspartitioned and dried over magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was subjected to silicagel column chromatography to give5-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.

EXAMPLE 143

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 9 and1-(4-fluorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-methyl-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.69-1.82(6H,m), 2.37-2.45(4H,m), 2.57-2.65(8H,m),3.10-3.14(4H,m), 3.75(3H,s), 6.83-6.99(4H,m)

EXAMPLE 144

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtainedin Staring Material Synthesis Example 9 and 1-(4-chlorophenyl)piperazinewere used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionicacid obtained in Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-methyl-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.76(6H,m), 2.42(4H,m), 2.56-2.65(8H,m), 3.18(4H,m),3.76(3H,s), 6.83(2H,d, J=7 Hz), 7.18(2H,d, J=7 Hz)

EXAMPLE 145

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 9 and1-(4-methylphenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,4,5,6,7-tetrahydro-2-methyl-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-2H-indazoleis obtained.

EXAMPLE 146

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-methyl-2H-indazol-3-yl)propionic acid obtainedin Stating Material Synthesis Example 9 and 1-phenylpiperazine a usedinstead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 1 and₄-(4-chlorophenyl)piperidine,4,5,6,7-tetrahydro-2-methyl-3-(3-(4-phenylpiperazin-1yl)propyl)-2H-indazoleis obtained.

EXAMPLE 147

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazol-3-yl)propionic acidobtained in Staring Material Synthesis Example 10 and1-(4-chlorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazolewas obtained, m.p. 101-103° C.

EXAMPLE 148

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 10 and1-(4-fluorophenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-(2-pyridyl)-2H-indazoleis obtained.

EXAMPLE 149

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 11 and1-(4-chlorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-phenyl-2H-indazolewas obtained, m.p. 127-129° C.

EXAMPLE 150

In the same manner as in Example 102 except that3-(4,5,6,7-tetrahydro-2-phenyl-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 11 and1-(4-fluorophenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in StaringMaterial Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-phenyl-2H-indazoleis obtained.

EXAMPLE 151

In the same manner as in Example 102 except that3-(2-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 12 and1-(4-chlorophenyl)piperazine were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,2-(4-chlorophenyl)-3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained, m.p. 129-131° C.

EXAMPLE 152

In the same manner as in Example 102 except that3-(2-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 12 and1-(4-fluorophenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,2-(4-chlorophenyl)-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazoleis obtained.

EXAMPLE 153

To a solution of3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole (1.0 g)obtained in Starting Material Synthesis Example 13 and1-(4-chlorophenyl)piperazine hydrochloride (0.9 g) in dimethylformamide(10 ml) was added potassium carbonate (1.1 g) and the mixture wasstirred at 60° C. for 3 hours. The reaction mixture was concentrated andthe residue was extracted with chloroform, washed with water, dried overmagnesium sulfate and concentrated. The obtained3-(4-(4-chlorophenyl)piperazin-1-yl)propionyl4,5,6,7-tetrahydro-1-methyl-1H-indazole(0.9 g) was dissolved in methanol (10 ml) and chloroform (10 ml), andsodium borohydride (0.7 g) was added under ice-cooling. After thecompletion of the reaction, the solvent was evaporated under reducedpressure and chloroform and aqueous potassium carbonate solution wereadded. The chloroform layer was partitioned and dried over magnesiumsulfate. The solvent was evaporated under reduced pressure, andisopropyl ether was added to the obtained residue. The precipitatedcrystals were collected by filtration to give 0.9 g of crude crystals of3-(1-hydroxy-3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole.

Sodium iodide (1.5 g) was dissolved in acetonitrile (12 ml) andchlorotrimethylsilane (1.3 ml) was added at room temperature withstirring. The above-mentioned compound (0.6 g) was further added. Thereaction mixture was refluxed under heating for 2 hours and cooled. Anaqueous sodium sulfite solution and an aqueous potassium carbonatesolution were added and the mixture was extracted with ethyl acetate.The solution was dried over magnesium sulfate and the solvent wasevaporated under reduced pressure. The residue was subjected to silicagel column chromatography to give3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole.

This compound could be also obtained by the following method. That is,4-(4-chlorophenyl)-1-(4-oxo-4-(2-oxocyclohexyl)butyryl)piperazineobtained by using 4-oxo4-(2-oxocyclohexyl)-n-butyric acid and1-(4-chlorophenyl)piperazine instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid and4-(4-chlorophenyl)piperidine used in Example 102 was refluxed underheating in a methanol solvent with methyl hydrazine. After thecompletion of the reaction, the solvent was evaporated under reducedpressure to give an oily substance. This compound was dissolved intetrahydrofuran and thereto was added lithium aluminum hydride in an icebath. After the completion of the reaction, a mixture oftetrahydrofuran—water was added, and then ethyl acetate and magnesiumsulfate were further added. The reaction mixture was filtered throughcelite, and the solvent was evaporated under reduced pressure. Theobtained residue was subjected to silica gel column chromatography togive3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole.

¹H-NMR(CDCl₃)δ: 1.72(2H,m), 1.78-1.88(4H,m), 2.38-2.64(12H,m),3.16(4H,m), 3.68(3H,s), 6.83(2H,d,J=7 Hz), 7.18(2H,d,J=7 Hz)

EXAMPLE 154

In the same manner as in Example 153 except that1-(4-fluorophenyl)piperazine was used instead of 1-(4halophenyl)piperazine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.90(6H,m), 2.33-2.70(12H,m), 3.10-3.14(4H,m),3.66(3H,s), 6.83-6.98(4H,m)

EXAMPLE 155

In the same manner as in Example 153 except that1-(4-methylphenyl)piperazine is used instead of1-(4-chlorophenyl)piperazine,4,5,6,7-tetrahydro-1-methyl-3-(3-(4-(4-methylphenyl)piperazine-1-yl)propyl)-1H-indazoleis obtained.

EXAMPLE 156

In the same manner as in Example 153 except that 1-phenylpiperazine isused instead of 1-(4-chlorophenyl)piperazine,4,5,6,7-tetrahydro-1-methyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1H-indazoleis obtained.

EXAMPLE 157

In the same manner as in Example 153 except that3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-phenyl-2H-indazole obtainedin Stating Material Synthesis Example 14 was used instead of3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole obtainedin Starting Material Synthesis Example 13, and then by a conventionaltreatment using maleic acid,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazolemaleate was obtained. In the same manner as in Example 153 except thatphenylhydrazine was used instead of methylhydrazine, and then by aconventional treatment using maleic acid,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazolemaleate, m.p. 150-151° C.

EXAMPLE 158

In the same manner as in Example 157 except that1-(4-fluorophenyl)piperazine is used instead of1-(4-chlorophenyl)piperazine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazoleis obtained.

EXAMPLE 159

In the same manner as in Example 157 except that1-(4-methylphenyl)piperazine is used instead of1-(4-chlorophenyl)piperazine,4,5,6,7-tetrahydro-1-phenyl-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-1H-indazoleis obtained.

EXAMPLE 160

In the same manner as in Example 157 except that 1-phenylpiperazine isused instead of 1-(4-chlorophenyl)piperazine, 4,5,6,7-tetrahydro1-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1H-indazole is obtained.

EXAMPLE 161

To a solution of1-benzenesulfonyl-3-(3-chloropropionyl)-4,5,6,7-tetrahydroindole (2.0 g)obtained in Starting Material Synthesis Example 15 and1-(4-chlorophenyl)piperazine hydrochloride (1.9 g) in dimethylformamide(20 ml) was added potassium carbonate (2.1 g) and the mixture wasstirred for 3 hours at 60° C. The reaction of was concentrated,extracted with chloroform, washed with water, dried over magnesiumsulfate and concentrated. The residue[(3-(4-(4-chlorophenyl)piperazine-1-yl)propionyl-4,5,6,7-tetrahydro-1-phenylsulfonyl-indole)-]was added to dioxane (20 ml) and 5M sodium hydroxide (20 ml), and themixture was stirred for 20 hours at room temperature. The reactionmixture was extracted with ethyl acetate, dried over magnesium sulfateand concentrated under reduced pressure. The obtained3-(4-(4-chlorophenyl)piperazin-1-yl)propionyl-4,5,6,7-tetrahydroindole(1.7 g) was dissolved in methanol (20 ml) and chloroform (20 ml), sodiumborohydride (1.4 g) was added thereto in an ice bath. After thecompletion of the reaction, the solvent was evaporated under reducedpressure, and chloroform and an aqueous potassium carbonate solutionwere added and the chloroform layer was partitioned. After drying overmagnesium sulfate, the solvent was evaporated under reduced pressure,and isopropyl ether was added to the obtained residue. The precipitatedcrystals were collected by filtration to give 1.3 g of crude crystals of3-(1-hydroxy-3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole.

Sodium iodide (1.5 g) was dissolved in acetonitrile (12 ml) andchlorotrimethylsilane (1.3 ml) was added with stirring at roomtemperature and the above-mentioned compound (0.6 g) was further added.The reaction mix was refluxed under heating for 2 hours and cooled. Anaqueous sodium sulfite solution and an aqueous potassium carbonatesolution were added and extracted with ethyl acetate. The solution wasdried over magnesium sulfate and the solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography to give3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole.

EXAMPLE 162

In the same manner as in Example 161 except that1-(4-fluorophenyl)piperazine is used instead of1-(4-chlorophenyl)piperazine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindoleis obtained.

EXAMPLE 163

In the same manner as in Example 161 except that1-(4-methylphenyl)piperazine is used instead of1-(4-chlorophenyl)piperazine,4,5,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)indoleis obtained.

EXAMPLE 164

In the same manner as in Example 161 except that 1-phenylpiperazine isused instead of 1-(4-chlorophenyl)piperazine,4,5,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)indole isobtained.

EXAMPLE 165

3-(3-(4-(4-Chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole(0.5 g) obtained in Example 161 and potassium carbonate (0.6 g) weredissolved in dimethylformamide (10 ml) and methyl iodide (0.3 g) wasadded under ice-cooling with stirring. The reaction mixture was stirredat room temperature for 2 hours and the solvent was evaporated underreduced pressure. Chloroform and an aqueous potassium carbonate solutionwere added and the chloroform layer was separated. The layer was driedover magnesium sulfate and the solvent was evaporated under reducedpressure. The residue was subjected to silica gel column chromatographyto give3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methylindole.

EXAMPLE 166

In the same manner as in Example 165 except that3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindoleis used instead of3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methylindoleis obtained.

EXAMPLE 167

In the same manner as in Example 165 except that4,5,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)indoleis used instead of3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole,4,5,6,7-tetrahydro-1-methyl-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)indoleis obtained.

EXAMPLE 168

In the same manner as in Example 165 except that4,5,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)indole is usedinstead of3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole,4,5,6,7-tetrahydro-1-methyl-3-(3-(4-phenylpiperazin-1-yl)propyl)indoleis obtained.

EXAMPLE 169

3-(3-(4-(4-Chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole(0.5 g) obtained in Example 161 and triethylamine (0.6 ml) weredissolved in dichloromethane (10 ml) and acetyl chloride (0.3 g) wasadded under ice-cooling with stirring. The reaction mixture was stirredfor 2 hours at room temperature and an aqueous potassium carbonatesolution is added, and the chloroform layer was separated. After dryingover magnesium sulfate, the solvent was evaporated under reducedpressure, and the obtained residue was subjected to silica gel columnchromatography to give1-acetyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole.

EXAMPLE 170

In the same manner as in Example 169 except that3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindoleis used instead of3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole,1-acetyl-3-(3-(4-(4-fluorophenyl)piperazine-1-yl)propyl)-4,5,6,7-tetrahydroindoleis obtained.

EXAMPLE 171

In the same manner as in Example 169 except that4,5,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)indoleis used instead of3-(3-(4(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole,1-acetyl-4,5,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)indoleis obtained.

EXAMPLE 172

In the same manner as in Example 169 except that4,5,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)indole is usedinstead of3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole,1-acetyl-4,5,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)indoleis obtained.

EXAMPLE 173

(3-(4,5,6,7-Tetrahydropyrazolo[2,3-a]pyridin-3-yl)-3-oxypropyl)trimethylammonium iodide (1.2 g) obtained in Starting Material Synthesis Example16 and 1-(4-fluorophenyl)piperazine (0.7 g) were suspended in methanol(20 ml) and the mixture was refluxed under heating for 4 hours. Thesolvent was evaporated under reduced pressure and chloroform and anaqueous potassium carbonate solution were added. The chloroform layerwas separated and dried over magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was subjected tosilica gel column chromatography to give 1.0 g of3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propionyl)-4,5,6,7-tetrahydropyrazolo[2,3-a]pyridine,m.p. 141-142° C.

This compound (0.9 g) was dissolved in methanol (10 ml) and chloroform(10 ml) and thereto was added sodium borohydride (0.7 g) in an ice bath.After the completion of the reaction, the solvent was evaporated underreduced pressure and chloroform and an aqueous potassium carbonatesolution were added. The chloroform layer was separated and dried overmagnesium sulfate. The solvent was evaporated under reduced pressure andisopropyl ether was added to the obtained residue. The precipitatedcrystals were collected by filtration to give 1.0 g of3-(1-hydroxy-3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydropyrazolo[2,3-a]pyridine,m.p. 130-131° C.

Sodium iodide (1.5 g) was dissolved in acetonitrile (12 ml) andchlorotrimethylsilane (1.3 ml) was added at room temperature withstirring. The above-mentioned compound (0.6 g) was further added. Thereaction mixture was refluxed under heating for 2 hours and cooled. Anaqueous sodium sulfite solution and an aqueous potassium carbonatesolution were added and the mixture was extracted with ethyl acetate.The solution was dried over magnesium sulfate and evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography to give3-(3-(4-(4fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydropyrazolo[2,3-a]pyridine.

¹H-NMR(CDCl₃)δ: 1.70-1.92(4H,m), 1.97-2.06(2H,m), 2.37-2.45(4H,m),2.58-2.70(6H,m), 3.11-3.17(4H,m), 4.08-4.16(2H,m), 6.84-6.99(4H,m),7.29(1H,s)

EXAMPLE 174

In the same manner as in Example 173 except that1-(4-methylphenyl)piperazine is used instead of1-(4-fluorophenyl)piperazine,4,5,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)pyrazolo[2,3-a]pyridineis obtained.

EXAMPLE 175

In the same manner as in Example 173 except that1-(4-chlorophenyl)piperazine is used instead of1-(4-fluorophenyl)piperazine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydropyrazolo[2,3-a]pyridineis obtained.

EXAMPLE 176

In the same manner as in Example 173 except that 1-phenylpiperazine isused instead of 1-(4-fluorophenyl)piperazine,4,5,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)pyrazolo[2,3-a]pyridineis obtained.

EXAMPLE 177

In the same manner as in Example 173 except that(3-(4,5,6,7-tetrahydro-2-methylpyrazolo[2,3-a]pyridin-3-yl)-3-oxypropyl)trimethylammonium iodide is used instead of(3-(4,5,6,7-tetrahydropyazolo[2,3-a]pyridin-3-yl)-3oxypropyl)trimethylammonium iodide obtained in Stating Material Synthesis Example 16,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-methylpyrazolo[2,3-a]pyridineis obtained.

EXAMPLE 178

In the same manner as in Example 173 except that(3-(4,5,6,7-tetrahydro-2-phenylpyrazolo[2,3-a]pyridin-3-yl)-3-oxypropyl)trimethylammonium iodide is used instead of(3-(4,5,6,7-tetrahydropyrazolo[2,3-a]pyridin-3-yl)-3-oxypropyl)trimethylammonium iodide obtained in Staring Material Synthesis Example 16,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2-phenylpyrazolo[2,3-a]pyridineis obtained.

EXAMPLE 179

In the same manner as in Example 153 except that3-(3-chloropropionyl)-5,6,7,8-tetrahydroindolidine obtained in StartingMaterial Synthesis Example 17 is used instead of3-(3-chloropropionyl)-4,5,6,7-tetrahydro-1-methyl-1H-indazole obtainedin Starting Material Synthesis Example 13,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydroindolidineis obtained.

EXAMPLE 180

In the same manner as in Example 179 except that1-(4-fluorophenyl)piperazine is used instead of1-(4chlorophenyl)piperazine,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-5,6,7,8-tetrahydroindolidineis obtained.

EXAMPLE 181

In the same manner as in Example 179 except that1-(4-methylphenyl)piperazine is used instead of1-(4chlorophenyl)piperazine5,6,7,8-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)indolamineis obtained.

EXAMPLE 182

In the same manner as in Example 179 except that 1-phenylpiperazine isused instead of 1-(4-chlorophenyl)piperazine,5,6,7,8-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)indolamine isobtained.

EXAMPLE 183

In the same manner as in Example 102 except that3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 4 and 1-(4-chlorophenyl)piperazinewere used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionicacid obtained in Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine, and then by a conventional treatment usinghydrochloric acid,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazolehydrochloride was obtained, m.p. 228-230° C.

EXAMPLE 184

In the same manner as in Example 102 except that3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 4 and 1-phenylpiperazine are usedinstead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,2,4,5,6-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)cyclopentapyrazoleis obtained.

EXAMPLE 185

In the same manner as in Example 102 except that3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 5 and1-(4-methylphenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,2,4,5,6,7,8-hexahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)cycloheptapyrazoleis obtained.

EXAMPLE 186

In the same manner as in Example 102 except that3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 5 and1-(4-chlorophenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazolis obtained.

EXAMPLE 187

In the same manner as in Example 102 except that3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 5 and 1-phenylpiperazine are usedinstead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,2,4,5,6,7,8-hexahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)cycloheptapyrazoleis obtained.

EXAMPLE 188

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 6 and1-(4-methylphenyl)piperazine are used instead of 3-(4,5,6,7-tetrahydro2H-indazol-3-yl)propionic acid obtained in Starting Material SynthesisExample 1 and 4-(4-chlorophenyl)piperidine,2,4,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)pyrano[4,3-c]pyrazoleis obtained.

EXAMPLE 189

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 6 and1-(4-chlorophenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazoleis obtained.

EXAMPLE 190

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydropyrano[4,3-c]pyrazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 6 and 1-phenylpiperazine are usedinstead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtainedin Starting Material Synthesis Example 1 and4-(4-chlorophenyl)piperidine,2,4,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)pyrano[4,3-c]pyrazoleis obtained.

EXAMPLE 191

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 7 and1-(4-methylphenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,2,4,6,7-tetrahydro-3-(3-(4-(4-methylphenyl)piperazine-1-yl)propyl)thiopyrano[4,3-c]pyrazoleis obtained.

EXAMPLE 192

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 7 and1-(4-chlorophenyl)piperazine are used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained inStarting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazoleis obtained.

EXAMPLE 193

In the same manner as in Example 102 except that3-(2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 7 and 1-phenylpiperazineare used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 1 and 4-(4halophenyl)piperidine,2,4,6,7-tetrahydro-3-(3-(4-phenylpiperazin-1-yl)propyl)thiopyrano[4,3-c]pyrroleis obtained.

EXAMPLE 194

To a mixture of3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole(3.1 g), dimethylformamide (30 ml) and triethylamine (2.5 ml) wasdropwise added acetyl chloride (0.72 ml) under ice-cooling. The mixturewas stirred as it was for 30 minutes. The reaction mixture was pouredinto ice water (200 ml). The mixture was extracted with ethyl acetate,washed with water and dried over anhydrous magnesium sulfate. Thefiltrate was concentrated under reduced pressure to give 3.4 g of anoily substance. The oil was subjected to silica gel columnchromatography (eluent; hexane:ethyl acetate=1:2) to give 0.60 g of1-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1H-indazole(component eluted later (compound A)), and 0.30 g of2-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole(component eluted first (compound B)).1-Acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1H-indazole(compound A: m.p. 60-61° C.);2-Acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole(compound B: m.p. 104-106° C.).

EXAMPLE 195

In the same manner as in Example 194 except that benzoyl chloride (1.2ml) was used instead of acetyl chloride, 1.0 g of1-benzoyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1H-indazole (component eluted later compound A), and 0.45 g of2-benzoyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole(component eluted first: compound B) were obtained.1-Benzoyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1H-indazole(compound A: m.p. 71-72° C.);2-Benzoyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole(compound B: m.p. as maleate 147-148° C.).

EXAMPLE 196

Lithium diisopropylamide solution prepared from diisopropylamine (2.8ml) and 1 M n-butyl lithium (11 ml) in tetrahydrofuran (40 ml) wascooled to −78° C. and cyclohexanone (2.0 ml) was added. The mixture wasstirred at −78° C. for 1 hour and1-tert-butoxycarbonyl-4-imidazocarbonylpiperidine (4.8 g) prepared fromN-tert-butoxycarbonylisonipecotic acid was added. The mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated and water was added to the obtained residue. The mixturewas extracted with ethyl acetate and the extract was dried overanhydrous magnesium sulfate. The filtrate was concentrated under reducedpressure to give 3.8 g of an oily substance. The oil was subjected tosilica gel column chromatography (eluent; chloroform:methanol=20:1) togive 2-((1-tert-butoxycarbonylpiperidin-4-yl)carbonyl)cyclohexanone,m.p. 71-72° C.

2-((l-tert-Butoxycarbonylpiperidin-4-yl)carbonyl)cyclohexanone (1.0 g)was dissolved in trifluoroacetic acid (10 ml) and the solution wasstirred at room temperature for 30 minutes. The solvent was evaporatedand the residue was made alkaline with an aqueous potassium carbonatesolution and extracted with ethyl acetate. After drying over magnesiumsulfite, the solvent was evaporated under reduced pressure,dimethylformamide (10 ml), 4-fluorophenylacetic acid (0.5 g) andtriethylamine (0.9 ml) were added to the obtained residue. Diethylcyanophosphate (0.5 ml) was added dropwise in an ice bath while stirringthe mixture. The mixture was stirred further for 3 hours. After thecompletion of the reaction, the solvent was evaporated under reducedpressure, and water was added to the obtained residue. The mixture wasextracted with chloroform and the extract was dried over magnesiumsulfate. The solvent was evaporated under reduced pressure. To asolution (50 ml) of the obtained2-((1-(2-(4-fluorophenyl)-acetyl)piperidin-4-yl)carbonyl)cyclohexanonein ethanol was added hydrazine hydrate (0.2 g) and the mixture wasrefluxed for 1 hour. The solvent was evaporated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography to give3-(1-(2-(4-fluorophenyl)acetyl)piperidin-4-yl)-4,5,6,7-tetrahydro-2H-indazole.

¹H-NMR(CDCl₃)δ: 1.45-1.98(8H,m), 2.39(2H,t,J=6 Hz), 2.59(2H,t,J=6 Hz),2.63-2.91(2H,m), 3.14(2H,dt,J=3.13 Hz), 3.72(2H,s), 3.94(1H,d,J=14 Hz),4.78(1H,d,J=14 Hz), 6.93-7.06(2H,m), 7.18-7.30(2H,m)

To a solution of the obtained3-(1-(2-(4-fluorophenyl)acetyl)piperidin-4-yl)-4,5,6,7-tetrahydro-2H-indazolein tetrahydrofuran was added lithium aluminum hydride under ice-coolingwith stirring, and the mixture was stirred at room temperature for 1hour. After the completion of the reaction, the reaction mixture wastreated with a mixed solvent of water—tetrahydrofuran and filteredthrough celite. The filtrate was concentrated under reduced pressure,and the obtained residue was subjected to silica gel columnchromatography to give3-(1-(2-(4-fluorophenyl)ethyl)piperidin-4-yl)-4,5,6,7-tetrahydro-2H-indazoledihydrochloride monohydrate, m.p. 143-145° C.

EXAMPLE 197

4-Oxo-4-(2-oxocyclohexyl)-n-butyric acid (4.0 g) and1-(4-fluorophenyl)piperazine (3.6 g) were used instead of3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Example102 and 4-(4-chlorophenyl)piperidine, 7.4 g of4-(4-fluorophenyl)-1-(4-oxo-4-(2-oxocyclohexyl)butyryl)piperazine wasobtained.

This compound (3.6 g) was refluxed under heating for 5 hours in methanol(100 ml) in the presence of hydroxylamine hydrochloride (3.2 g) andtriethylamine (6.3 ml). After the completion of the reaction, thesolvent was evaporated under reduced pressure and an aqueous potassiumcarbonate solution was added to the residue. The mixture was extractedwith chloroform and the extract was dried over magnesium sulfate. Thesolvent was evaporated under reduced pressure to give 3.5 g of an oilysubstance. This compound and triethylamine (5.2 ml) were dissolved inethylene dichloride (50 ml), and methanesulfonyl chloride (1.4 ml) wasdropwise added under ice-cooling. After the completion of the reaction,the solvent was evaporated under reduced pressure, and an aqueouspotassium carbonate solution was added to the residue. The mixture wasextracted with chloroform and the extract was dried over magnesiumsulfate. The solvent was evaporated under reduced pressure to give 3.7 gof an oily substance.

This compound was dissolved in tetrahydrofuran (50 ml), and lithiumaluminum hydride (1.5 g) was added under ice-cooling. After thecompletion of the reaction, a mixed solution of tetrahydrofuran—water,then ethyl acetate, and magnesium sulfate were added, and the mixturewas filtered through celite. The solvent was evaporated under reducedpressure. The obtained residue was subjected to silica gel columnchromatography to give3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[c]isoxazole (component eluted first: compound A), and3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydrobenzo[d]isoxazole(component eluted later: compound B) from the eluate ofchloroform:methanol=50:1.

Compound; ¹H-NMR(CDCl₃)δ: 1.67-1.82(4H,m),1.84-1.95(2H,m),2.35-2.46(4H,m), 2.56-2.60(4H,m), 2.69-2.75(4H,m), 3.09-3.13(4H,m),6.83-7.00(4H,m)

Compound B; ¹H-NMR(CDCl₃)δ: 1.70-1.96(6H,m), 2.34-2.52(4H,m),2.57-2.75(8H,m), 3.11-3.14(4H,m), 6.84-6.99(4H,m)

EXAMPLE 198

In the same manner as in Example 102 except that4-(4,5,6,7-tetrahydro-2H-indazol-3-yl)-n-butyric acid obtained inStarting Material Synthesis Example 3 and 1-(2-pyridyl)piperazine wereused instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acidobtained in Starting Material Synthesis Example 1 and4-(4chlorophenyl)piperidine,3-(4-(4-(2-pyridyl)piperazin-1-yl)butyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.55-1.80(8H,m), 2.34-2.44(4H,m), 2.52-2.64(8H,m),3.53-3.57(4H,m), 6.58-6.65(2H,m), 7.43-7.49(1H,m), 8.18(1H,dd,J=2.6 Hz)

EXAMPLE 199

In the same manner as in Example 102 except that 1-(2-pyridyl)piperazinewas used instead of 4-(4-chlorophenyl)piperidine,3-(3-(4-(2-pyridyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.66-1.92(6H,m), 2.40-2.48(4H,m), 2.56-2.72(8H,m),3.55-3.59(4H,m), 6.59-6.65(2H,m), 7.43-7.50(1H,m), 8.18(1H,dd,J=2.4 Hz)

EXAMPLE 200

In the same manner as in Example 102 except that1-(4chlorophenyl)-3-methylpiperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(4-chlorophenyl)-2-methylpiperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.01(3H,d,J=6 Hz), 1.68-1.94(6H,m), 2.30-2.56(6H,m),2.58-2.73(5H,m), 2.79-2.89(1H,m), 3.10-3.23(2H,m), 3.78-3.88(1H,m),6.83(2H,d,J=9 Hz), 7.19(2H,d,J=9 Hz)

EXAMPLE 201

In the same manner as in Example 102 except that 4-phenylpiperadine wasused instead of 4-(4-chlorophenyl)piperidine,3-(3-(4-phenylpiperidin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole wasobtained.

¹H-NMR(CDCl₃)δ: 1.69-1.92(10H,m), 1.98-2.13(2H,m), 2.40-2.52(5H,m),2.61-2.71(4H,m), 3.02-3.24(2H,m), 7.14-7.34(5H,m)

EXAMPLE 202

3-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole(0.5 g) obtained in Example 138 was dissolved in formic acid (5 ml) and30% hydrogen peroxide (0.27 ml) was dropwise added under ice-cooling,and the mixture was stirred for 30 minutes at not more than 5° C. Thereaction mixture was poured into ice water, made alkaline with potassiumcarbonate and extracted with ethyl acetate. After drying over magnesiumsulfate, the solution was concentrated and recrystallized from isopropylalcohol:isopropyl ether (1:2) to give3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydrothiopyrano[4,3-c]pyrazole5-oxide, m.p. 140-142° C.

EXAMPLE 203

In the same manner as in Example 102 except that1-(2,3-dichlorophenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,3-(3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.95(6H,m), 2.43(2H,t,J=6 Hz), 2.51(2H,t,J=7 Hz),2.56-2.77(8H,m), 3.02-3.16(4H,m), 6.92-6.99(1H,m), 7.08-7.17(2H,m)

EXAMPLE 204

In the same manner as in Example 102 except that1-(2,3-dimethylphenyl)piperazine was used instead of4-(4-chlorophenyl)piperidine,4,5,6,7-tetrahydro-3-(3-(4-(2,3-dimethylphenyl)piperazin-1-yl)propyl)-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.68-1.92(6H,m), 2.21(3H,s), 2.26(3H,s), 2.43(2H,t,J=6Hz), 2.49(2H,t,J=7 Hz), 2.55-2.76(8H,m), 2.89-3.02(4H,m), 6.99(1H,d,J=7Hz), 6.93(1H,d, J=9 Hz), 7.07(1H,dd,J=9.7 Hz)

EXAMPLE 205

In the same manner as in Example 133 exceptthat-1-(2,3-dimethyl-phenyl)piperazine was used instead of1-(4-fluorophenyl)piperazine,3-(4-(4-(2,3-dimethylphenyl)piperazin-1-yl)butyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.56-1.83(8H,m), 2.26(3H,s), 2.34(3H,s),2.41-2.46(4H,m), 2.57-2.64(8H,m), 2.90-2.94(4H,m), 6.90(2H,t,J=8 Hz),7.07(1H,t,J=8 Hz)

EXAMPLE 206

In the same manner as in Example 133 except that1-(2,3-dichloro-phenyl)piperazine was used instead of1-(4-fluorophenyl)piperazine,3-(4-(4(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4,5,6,7-tetrahydro-2H-indazolewas obtained.

¹H-NMR(CDCl₃)δ: 1.53-1.88(8H,m), 2.41-2.47(4H,m), 2.57-2.65(8H,m),3.07-3.10(4H,m), 6.96(1H,dd,J=3.6 Hz), 7.13-7.15(2H,m)

FORMULATION EXAMPLE 1

The inventive compound (0.5 part), lactose (25 parts), crystallinecellulose (35 parts) and corn starch (3 parts) were thoroughly admixedand kneaded well with a binder prepared from corn starch (2 parts). Thekneaded product was passed through a 16 mesh sieve, dried in an oven at50° C. and passed through a 24 mesh sieve. The kneaded powder thusobtained, corn starch (8 parts), crystalline cellulose (11 parts) andtalc (9 parts) were thoroughly admixed and compressed to give tabletscontaining 0.5 mg of an active ingredient per tablet.

FORMULATION EXAMPLE 2

The inventive compound (1.0 mg) and sodium chloride (9.0 mg) aredissolved in injectable water, and the solution is filtered to removepyrogen. The filtrate is aseptically charged in ampoules and sterilized,which is followed by melt-sealing of the ampoules to give injectionscontaining 1.0 mg of an active ingredient.

The superior pharmacological activity of the compound of the formula (I)was evaluated by the following series of receptor binding tests,anti-methamphetamine action, catalepsy induction and suppressive effecton neurotoxicity by MK-801.

EXPERIMENTAL EXAMPLE 1 Affinity for D₄ Receptor; ³H-spiperone Binding

The D₄ receptor expression cell membrane specimen and ³H-spiperone wereincubated at 27° C. for 2 hours in the presence of a test compound.Immediately after the completion of the reaction, the reaction mixturewas filtered through a Whatman GF/B filter (trademark) by suction andthe radioactivity on the filter was determined on a liquid scintillationcounter. The amount of non-specific binding was determined in thepresence of 10 μM haloperidol. The concentration of the test compoundnecessary for inhibiting by 50% (IC₅₀) was calculated from nonlinearregression curve, based on which the inhibition constant (Ki value) wasdetermined.

EXPERIMENTAL EXAMPLE 2 Affinity for D₂ Receptor; ³H-spiperone Binding

Preparation of crude synaptic membrane and binding test followed themethod of I. Creese et al., European Journal of Pharmacology, vol. 46,p. 377 (1977). The crude synaptic membrane was prepared from thecryopreserved striate body from rats and the membrane sample and³H-spiperone were reacted at 37° C. for 20 minutes in the presence of atest compound. Immediately after the completion of the reaction, thereaction mixture was filtered through a Whatman GF/B filter (trademark)by suction and the radioactivity on the filter was determined on aliquid scintillation counter. The amount of non-specific binding wasdetermined in the presence of 100 μM(±)-sulphide. The concentration ofthe test compound necessary for 50% inhibiting (IC₅₀) was calculatedfrom nonlinear regression curve, based on which the inhibition constant(Ki value) was determined.

As a result of Experimental Examples 1 and 2, the inventive compoundshowed a Ki value for D₄ receptor of 0.01-10 nM, whereas it was not lessthan 10 nM for D₂ receptor. Therefore, the inventive compound wasconfirmed to have a stronger affinity for D₄ receptor than for D₂receptor. In contrast, Dapiprazole barely showed affinity for D₄receptor or D₂ receptor.

EXPERIMENTAL EXAMPLE 3 Affinity for 5-HT₂ Receptor

A specific serotonin 2 (5-HT₂) receptor binding test followed the methodof Mol. Pharmacol., vol. 21, p. 301 (1981).

A crude synaptosome fraction was separated from hippocampus of 9-10week-old Wistar rats, and suspended in 50 mM Tris-HCl buffer (pH 7.7)for the experiment. The test compound in several concentrations andtritiated ketanserin (final concentration 0.2 nM) were added to thesynaptosome suspension, and each mixture was incubated at 37° C. for 20minutes. After the incubation, the mixture was filtered with suctionthrough Whatman GF/B (trademark) glass filter. The filter was washedwith 50 nM Tris-HCl buffer (pH 7.7), and the radioactivity of the filterwas measured by a liquid scintillation counter. Non-specific binding wasdetermined in the presence of 10⁻⁵ M mianserin. The concentrationnecessary for 50% inhibition (IC₅₀) was determined on a graph, andinhibition constant (Ki value) was calculated.

As a result, the inventive compound showed strong affinity of 0.01-50 nMfor 5-HT₂ Receptor.

EXPERIMENTAL EXAMPLE 4 Evaluation of Mouse Anti-methamphetamine Action(major effect)

Male ddY mice (20-30 g, 4 weeks of age, 15 mice per group) were used forthe experiment. A test compound was orally administered to the mice, andone hour later, an aqueous solution of methamphetamine (DAINIPPONPHARMACEUTICAL CO., LTD., 1 mg/kg) in physiological saline wassubcutaneously administered. Immediately thereafter, the mice wereplaced in a measurement apparatus equipped with a pair of infrared beamsand having an inner size of 25×15×14 (height) cm. The number ofcrossings through the infrared beams in 30 minutes from 10 minutes to 40minutes after initiation of observation was used as an index to showpromoted motion induced by methamphetamine, and the suppressive actionof the ED₅₀ value of the test compound was calculated.

As a result, the inventive compound showed a strong activity asexpressed by the ED₅₀ value of not more than 1.0 mg/kg (p.o.).

EXPERIMENTAL EXAMPLE 5 Evaluation of Catalepsy Induction (side effects)

Male ddY mice (20-30 g, 4 weeks of age, 8 per group) were used for thetest. A test compound was administered to the mice, and 1, 3, 5 and 7hours later, the time (catalepsy time) was measured for up to 30 secondsmaximum, during which time the forelimbs were placed on a bar fixed at aheight of 4 cm in the horizontal direction, and the body posture waskept at an angle of about 45 degrees. The strength of the catalepsyinduction of the test compound was evaluated by adding the catalepsytimes at 4 determination points at each dose (total time being a sumvalue) and calculating ED_(10s) by regression to the dose that made theaverage time 10 seconds.

As a result, ED_(10s) of the inventive compound was not less than 20mg/kg, indicating weak catalepsy induction.

EXPERIMENTAL EXAMPLE 6 Suppressive Effect on Neurotoxicity by MK-801

Female SD rats (200-300 g, 9-12 weeks of age) were used for the test. Anaqueous solution of the test compound (0.1 ml/kg) was intraperitoneallyadministered and an aqueous solution of (+)-MK-801 (0.5 mg/kg, 0.1ml/kg, Research Biochemicals International, Natick, Mass., USA) wassubcutaneously administered 15 minutes later. After 4 hours from theadministration of MK-80 1, the rats were anesthetized withpentobarbital. An injection needle was inserted into the left ventricleof the rats and left auricle was opened. After exsanguination byperfusion with physiological saline (ca. 100 ml), the rats were fixedunder perfusion with 4% paraformaldehyde ·1.5% glutalaldehyde ·0.1 Mphosphate buffer (ca. 400-500 ml). The head was opened and the brain wasremoved. A part including posterior cingulate convolution was cut outand placed in said fixative for postfixation. Upon paraffin embedding, athin section (3 μm) was prepared and stained with hematoxylin and eosin.After dehydration and sealing, the slide was observed with an opticalmicroscope.

As a result of the test, the inventive compound was found to suppressneurotoxicity (vacuolation of cells) of posterior cingulate convolution,which is observed on administration of an NMDA receptor antagonisticdrug MK-801. The test results reveal that the inventive compoundimproves degradation of NMDA receptor function.

EXPERIMENTAL EXAMPLE 7 Acute Toxicity

The inventive compound (100 mg/kg) was orally administered to 4 femaleSD rats (5 weeks of age) but no death was observed.

The inventive fused heterocyclic compound, an optical isomer thereof anda pharmaceutically acceptable salt thereof show a strong blocking actionon D₄ receptor and 5-HT₂ receptor, as well as blockage of NMDA receptorhyofunction. In addition, the inventive compound possesses apharmacological action, such as anti-methamphetamine action, that isnecessary as an antipsychotic agent, as well as a strong suppressiveaction on neurotoxicity induced by MK-801. On the other hand, catalepsyinduction in mice, which is an index of extrapyramidal side effects, wasfound to be extremely weak. The results indicate greater dissociation ofthe major effect from the side effects of the inventive compound.

From the foregoing results, it is clear that the inventive compounds canmake useful antipsychotic agents effective against not only positivesymptoms centering on hallucination and delusion characteristic of theacute stage of schizophrenia, but also negative symptoms of apathy,abulia and autism. They are expected to be highly safe antipsychoticagents associated with less side effects, such as extrapyramidalsymptoms and endocrine disturbance, which are observed when conventionalantipsychotic agents having D₂ receptor blocking action areadministered. Thus, the inventive compounds can be used as therapeuticagents for the diseases such as schizophrenia.

What is claimed is:
 1. A compound of the formula (I)

wherein R is a group having the following formula (3),

wherein Y is a linear or branched C₁-C₄ alkylene optionally having asubstituent R^(1a) at an optional position, wherein R^(1a) is alkyl,hydroxy, alkoxy, amino or alkylamino, A is void, or an oxygen atom, asulfur atom, SO, SO₂ or N—R⁷ wherein R⁷ is hydrogen, alkyl, arylalkyl oracyl, B is a linear or branched C₁-C₄ alkylene optionally having asubstituent R^(1b) at an optional position, wherein R^(1b) is alkyl,hydroxy, alkoxy, amino or alkylamino, and R³ is a hydrogen, an alkyl, anacyl or an aryl; D is void, or a linear or branched alkylene having 1 to8 carbon atoms; Q—T is CH₂—N; G is void, or a linear or branchedalkylene having 1 to 8 carbon atoms or a carbonyl; R⁵ is a hydrogen oran alkyl; and R⁶ is an optionally substituted aryl, an optionallysubstituted heteroaryl or an optionally substituted fused heteroaryl,the optional substituent being selected from the group consisting ofhalogen, haloalkyl, alkyl, alkoxy, hydroxy, nitro, amino, methylaminoand dimethylamino, an optical isomer thereof or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein, in theformula (I), R is a group having the formula (3), wherein Y is a linearor branched C₁-C₄ alkylene optionally having a substituent R^(1a) at anoptional position wherein R^(1a) is alkyl, A is void, or an oxygen atom,a sulfur atom or N—R⁷ wherein R⁷ is hydrogen, alkyl, arylalkyl or acyl,B is a linear or branched C₁-C₄ alkylene optionally having a substituentR^(1b) at an optional position, wherein R^(1b) is alkyl, and R³ is ahydrogen, an alkyl, an acyl or an aryl; D is void, or a linear orbranched alkylene having 1 to 8 carbon atoms; Q—T is CH₂—N; G is void;R⁵ is a hydrogen or an alkyl; and R⁶ is an optionally substituted aryl,an optionally substituted heteroaryl or an optionally substituted fusedheteroaryl, an optical isomer thereof or a pharmaceutically acceptablesalt thereof.
 3. The compound of claim 1, wherein, in the formula (I), Ris a group having the formula (3), wherein Y is a linear alkylene having1 to 4 carbon atoms, A is void, or an oxygen atom or N—R⁷ wherein R⁷ ishydrogen or acyl, B is a linear or branched alkylene having 1 to 4carbon atoms, and R³ is a hydrogen, an alkyl having 1 to 4 carbon atomsor an acyl; D is void, or a linear or branched alkylene having 1 to 8carbon atoms; Q—T is CH₂—N; G is void; R⁵ is a hydrogen or an alkylhaving 1 to 4 carbon atoms; and R⁶ is an optionally substituted aryl, anoptionally substituted heteroaryl or an optionally substituted fusedheteroaryl, an optical isomer thereof or a pharmaceutically acceptablesalt thereof.
 4. The compound of claim 1, wherein, in the formula (I), Ris a group having the formula (3), wherein Y is an ethylene, A is void,or an oxygen atom or N—R⁷ wherein R⁷ is hydrogen or acyl, B is a linearor branched alkylene having 1 to 3 carbon atoms, and R³ is a hydrogen oran alkyl having 1 to 4 carbon atoms; D is void, or a linear or branchedalkylene having 1 to 8 carbon atoms; Q—T is CH₂—N; G is void; R⁵ is ahydrogen or an alkyl having 1 to 4 carbon atoms; and R⁶ is an optionallysubstituted aryl, an optionally substituted heteroaryl or an optionallysubstituted fused heteroaryl, an optical isomer thereof or apharmaceutically acceptable salt thereof.
 5. The compound of claim 1,wherein, in the formula (I), R is a group having the formula (3),wherein Y is an ethylene, A is void, or an oxygen atom or N—R⁷ whereinR⁷ is hydrogen or acyl, B is a linear alkylene having 1 to 3 carbonatoms, and R³ is a hydrogen or a methyl; D is a trimethylene; Q—T isCH₂—N; G is void; R⁵ is a hydrogen; and R⁶ is an aryl optionally havinghalogen or alkyl having 1 to 4 carbon atoms, an optical isomer thereofor a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, which is a member selected from the group consisting of the followingcompounds:3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,3-(3-(4-(4-methylphenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,3-(3-(4-phenylpiperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole,3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,and5-acetyl-3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising the compound of claim 1, an optical isomerthereof or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable additive.
 8. A method for the treatment ofpsychosis which comprises administering to a patient in need of same,the compound according to claim
 1. 9. The compound of claim 1, which is3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-indazole.